1887

Abstract

Alum has been the most widely used adjuvant for over 80 years. Although there have been searches for alternative adjuvants, aluminium-containing adjuvants will continue to be used for many years due to their good track record of safety, low cost and adjuvanticity with a variety of antigens. For infections that can be prevented by induction of serum antibodies, aluminium-containing adjuvants formulated under optimal conditions are the adjuvants of choice. There are also some limitations of aluminium-containing adjuvants, which include local reactions, augmentation of IgE antibody responses, ineffectiveness for some antigens and inability to augment cell-mediated immune responses, especially cytotoxic T-cell responses. In this review, we describe the current knowledge regarding the mechanisms (both cellular and molecular) by which alum employs its adjuvant effect, although the final mechanism is not yet well-defined. Furthermore, we discuss how alum’s adjuvanticity could be improved.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2012-07-01
2024-04-19
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References

  1. Banchereau J., Steinman R. M. 1998; Dendritic cells and the control of immunity. Nature 392:245–252 [View Article][PubMed]
    [Google Scholar]
  2. Barth M. W., Hendrzak J. A., Melnicoff M. J., Morahan P. S. 1995; Review of the macrophage disappearance reaction. J Leukoc Biol 57:361–367[PubMed]
    [Google Scholar]
  3. Bendelac A., Medzhitov R. 2002; Adjuvants of immunity: harnessing innate immunity to promote adaptive immunity. J Exp Med 195:F19–F23 [View Article][PubMed]
    [Google Scholar]
  4. Brewer J. M., Conacher M., Satoskar A., Bluethmann H., Alexander J. 1996; 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 [View Article][PubMed]
    [Google Scholar]
  5. Burns K., Martinon F., Tschopp J. 2003; New insights into the mechanism of IL-1β maturation. Curr Opin Immunol 15:26–30 [View Article][PubMed]
    [Google Scholar]
  6. Calabro S., Tortoli M., Baudner B. C., Pacitto A., Cortese M., O’Hagan D. T., De Gregorio E., Seubert A., Wack A. 2011; Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. Vaccine 29:1812–1823 [View Article][PubMed]
    [Google Scholar]
  7. Carpenter G. W., Carr D. J. 1995; Pretreatment with β-funaltrexamine blocks morphine-mediated suppression of CTL activity in alloimmunized mice. Immunopharmacology 29:129–140 [View Article][PubMed]
    [Google Scholar]
  8. Didierlaurent A. M., Morel S., Lockman L., Giannini S. L., Bisteau M., Carlsen H., Kielland A., Vosters O., Vanderheyde N. other authors 2009; AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol 183:6186–6197 [View Article][PubMed]
    [Google Scholar]
  9. Duthie M. S., Windish H. P., Fox C. B., Reed S. G. 2011; Use of defined TLR ligands as adjuvants within human vaccines. Immunol Rev 239:178–196 [View Article][PubMed]
    [Google Scholar]
  10. Eisenbarth S. C., Colegio O. R., O’Connor W., Sutterwala F. S., Flavell R. A. 2008; Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453:1122–1126 [View Article][PubMed]
    [Google Scholar]
  11. Flach T. L., Ng G., Hari A., Desrosiers M. D., Zhang P., Ward S. M., Seamone M. E., Vilaysane A., Mucsi A. D. other authors 2011; Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat Med 17:479–487 [View Article][PubMed]
    [Google Scholar]
  12. Franchi L., Núñez G. 2008; The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1β secretion but dispensable for adjuvant activity. Eur J Immunol 38:2085–2089 [View Article][PubMed]
    [Google Scholar]
  13. Gavin A. L., Hoebe K., Duong B., Ota T., Martin C., Beutler B., Nemazee D. 2006; Adjuvant-enhanced antibody responses in the absence of Toll-like receptor signaling. Science 314:1936–1938 [View Article][PubMed]
    [Google Scholar]
  14. Glenny A., Pope C., Waddington H., Wallace U. 1926; Immunological notes. XVII. The antigenic value of toxoid precipitated by potassium alum. J Pathol Bacteriol 26:38–39
    [Google Scholar]
  15. Goto N., Akama K. 1982; Histopathological studies of reactions in mice injected with aluminum-adsorbed tetanus toxoid. Microbiol Immunol 26:1121–1132[PubMed] [CrossRef]
    [Google Scholar]
  16. Goto N., Akama K. 1984; Local histopathological reactions to aluminum-adsorbed tetanus toxoid. Naturwissenschaften 71:427–428 [View Article][PubMed]
    [Google Scholar]
  17. Goto N., Kato H., Maeyama J., Shibano M., Saito T., Yamaguchi J., Yoshihara S. 1997; Local tissue irritating effects and adjuvant activities of calcium phosphate and aluminium hydroxide with different physical properties. Vaccine 15:1364–1371 [View Article][PubMed]
    [Google Scholar]
  18. Gupta R. K., Chang A. C., Griffin P., Rivera R., Siber G. R. 1996; In vivo distribution of radioactivity in mice after injection of biodegradable polymer microspheres containing 14C-labeled tetanus toxoid. Vaccine 14:1412–1416 [View Article][PubMed]
    [Google Scholar]
  19. Heijmans S., De Meulemeester M., Reynders P., Giet D., Demanet E., Devresse P.-Y., Icardi G., Dramé M., Roman F., Gillard P. 2011; Immunogenicity profile of a 3.75-µg hemagglutinin pandemic rH5N1 split virion AS03A-adjuvanted vaccine in elderly persons: a randomized trial. J Infect Dis 203:1054–1062 [View Article][PubMed]
    [Google Scholar]
  20. Hornung V., Bauernfeind F., Halle A., Samstad E. O., Kono H., Rock K. L., Fitzgerald K. A., Latz E. 2008; Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9:847–856 [View Article][PubMed]
    [Google Scholar]
  21. Huber M., Beuscher H. U., Rohwer P., Kurrle R., Röllinghoff M., Lohoff M. 1998; Costimulation via TCR and IL-1 receptor reveals a novel IL-1α-mediated autocrine pathway of Th2 cell proliferation. J Immunol 160:4242–4247[PubMed]
    [Google Scholar]
  22. Hutchison S., Benson R. A., Gibson V. B., Pollock A. H., Garside P., Brewer J. M. 2012; Antigen depot is not required for alum adjuvanticity. FASEB J 26:1272–1279 [View Article][PubMed]
    [Google Scholar]
  23. Idzko M., Hammad H., van Nimwegen M., Kool M., Willart M. A. M., Muskens F., Hoogsteden H. C., Luttmann W., Ferrari D. other authors 2007; Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat Med 13:913–919 [View Article][PubMed]
    [Google Scholar]
  24. Jazani N. H., Parsania S., Sohrabpour M., Mazloomi E., Karimzad M., Shahabi S. 2011a; Naloxone and alum synergistically augment adjuvant activities of each other in a mouse vaccine model of Salmonella typhimurium infection. Immunobiology 216:744–751 [View Article][PubMed]
    [Google Scholar]
  25. Jazani N. H., Sohrabpour M., Mazloomi E., Shahabi S. 2011b; A novel adjuvant, a mixture of alum and the general opioid antagonist naloxone, elicits both humoral and cellular immune responses for heat-killed Salmonella typhimurium vaccine. FEMS Immunol Med Microbiol 61:54–62 [View Article][PubMed]
    [Google Scholar]
  26. Jenner E. 1909 The Three Original Publications on Vaccination Against Smallpox Cambridge, MA: Harvard Classics;
    [Google Scholar]
  27. Kool M., Pétrilli V., De Smedt T., Rolaz A., Hammad H., van Nimwegen M., Bergen I. M., Castillo R., Lambrecht B. N., Tschopp J. 2008a; Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol 181:3755–3759[PubMed] [CrossRef]
    [Google Scholar]
  28. Kool M., Soullié T., van Nimwegen M., Willart M. A. M., Muskens F., Jung S., Hoogsteden H. C., Hammad H., Lambrecht B. N. 2008b; Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med 205:869–882 [View Article][PubMed]
    [Google Scholar]
  29. Kool M., Willart M. A. M., van Nimwegen M., Bergen I., Pouliot P., Virchow J. C., Rogers N., Osorio F., Reis E Sousa C. other authors 2011; An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34:527–540 [View Article][PubMed]
    [Google Scholar]
  30. Krysko D. V., Agostinis P., Krysko O., Garg A. D., Bachert C., Lambrecht B. N., Vandenabeele P. 2011; Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol 32:157–164 [View Article][PubMed]
    [Google Scholar]
  31. Kundi M. 2007; New hepatitis B vaccine formulated with an improved adjuvant system. Expert Rev Vaccines 6:133–140 [View Article][PubMed]
    [Google Scholar]
  32. Kuroda E., Ishii K. J., Uematsu S., Ohata K., Coban C., Akira S., Aritake K., Urade Y., Morimoto Y. 2011; Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms. Immunity 34:514–526 [View Article][PubMed]
    [Google Scholar]
  33. Lambrecht B. N., Kool M., Willart M. A. M., Hammad H. 2009; Mechanism of action of clinically approved adjuvants. Curr Opin Immunol 21:23–29 [View Article][PubMed]
    [Google Scholar]
  34. Lamkanfi M., Kanneganti T.-D. 2010; Nlrp3: an immune sensor of cellular stress and infection. Int J Biochem Cell Biol 42:792–795 [View Article][PubMed]
    [Google Scholar]
  35. Leroux-Roels I., Borkowski A., Vanwolleghem T., Dramé M., Clement F., Hons E., Devaster J.-M., Leroux-Roels G. 2007; Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 370:580–589 [View Article][PubMed]
    [Google Scholar]
  36. Li H., Nookala S., Re F. 2007; Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1β and IL-18 release. J Immunol 178:5271–5276[PubMed] [CrossRef]
    [Google Scholar]
  37. Li H., Willingham S. B., Ting J. P. Y., Re F. 2008; Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J Immunol 181:17–21[PubMed] [CrossRef]
    [Google Scholar]
  38. Mannhalter J. W., Neychev H. O., Zlabinger G. J., Ahmad R., Eibl M. M. 1985; 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[PubMed]
    [Google Scholar]
  39. Mantovani A., Cassatella M. A., Costantini C., Jaillon S. 2011; Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531 [View Article][PubMed]
    [Google Scholar]
  40. Mariathasan S., Monack D. M. 2007; Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7:31–40 [View Article][PubMed]
    [Google Scholar]
  41. Marichal T., Ohata K., Bedoret D., Mesnil C., Sabatel C., Kobiyama K., Lekeux P., Coban C., Akira S. other authors 2011; DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med 17:996–1002 [View Article][PubMed]
    [Google Scholar]
  42. Martinon F., Pétrilli V., Mayor A., Tardivel A., Tschopp J. 2006; Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241 [View Article][PubMed]
    [Google Scholar]
  43. Matzinger P. 2002; The danger model: a renewed sense of self. Science 296:301–305 [View Article][PubMed]
    [Google Scholar]
  44. McKee A. S., MacLeod M., White J., Crawford F., Kappler J. W., Marrack P. 2008; Gr1+ IL-4-producing innate cells are induced in response to Th2 stimuli and suppress Th1-dependent antibody responses. Int Immunol 20:659–669 [View Article][PubMed]
    [Google Scholar]
  45. McKee A. S., Munks M. W., MacLeod M. K. L., Fleenor C. J., Van Rooijen N., Kappler J. W., Marrack P. 2009; Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol 183:4403–4414 [View Article][PubMed]
    [Google Scholar]
  46. Molitor T. W., Morilla A., Risdahl J. M., Murtaugh M. P., Chao C. C., Peterson P. K. 1992; Chronic morphine administration impairs cell-mediated immune responses in swine. J Pharmacol Exp Ther 260:581–586[PubMed]
    [Google Scholar]
  47. Monie A., Hung C.-F., Roden R., Wu T.-C. 2008; Cervarix: a vaccine for the prevention of HPV 16, 18-associated cervical cancer. Biologics 2:97–105[PubMed]
    [Google Scholar]
  48. Mosca F., Tritto E., Muzzi A., Monaci E., Bagnoli F., Iavarone C., O’Hagan D., Rappuoli R., De Gregorio E. 2008; Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci U S A 105:10501–10506 [View Article][PubMed]
    [Google Scholar]
  49. Munks M. W., McKee A. S., Macleod M. K., Powell R. L., Degen J. L., Reisdorph N. A., Kappler J. W., Marrack P. 2010; Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo . Blood 116:5191–5199 [View Article][PubMed]
    [Google Scholar]
  50. Nemazee D., Gavin A., Hoebe K., Beutler B. 2006; Immunology: Toll-like receptors and antibody responses. Nature 441:E4–, discussion E4 [View Article][PubMed]
    [Google Scholar]
  51. Palm N. W., Medzhitov R. 2009; Immunostimulatory activity of haptenated proteins. Proc Natl Acad Sci U S A 106:4782–4787 [View Article][PubMed]
    [Google Scholar]
  52. Pétrilli V., Papin S., Dostert C., Mayor A., Martinon F., Tschopp J. 2007; Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 14:1583–1589 [View Article][PubMed]
    [Google Scholar]
  53. Robinson R. T., Khader S. A., Locksley R. M., Lien E., Smiley S. T., Cooper A. M. 2008; Yersinia pestis evades TLR4-dependent induction of IL-12(p40)2 by dendritic cells and subsequent cell migration. J Immunol 181:5560–5567[PubMed] [CrossRef]
    [Google Scholar]
  54. Sacerdote P., Gaspani L., Panerai A. E. 2000a; The opioid antagonist naloxone induces a shift from type 2 to type 1 cytokine pattern in normal and skin-grafted mice. Ann N Y Acad Sci 917:755–763 [View Article][PubMed]
    [Google Scholar]
  55. Sacerdote P., Manfredi B., Gaspani L., Panerai A. E. 2000b; The opioid antagonist naloxone induces a shift from type 2 to type 1 cytokine pattern in BALB/cJ mice. Blood 95:2031–2036[PubMed]
    [Google Scholar]
  56. Schijns V. E. J. C., Lavelle E. C. 2011; Trends in vaccine adjuvants. Expert Rev Vaccines 10:539–550 [View Article][PubMed]
    [Google Scholar]
  57. Schnare M., Barton G. M., Holt A. C., Takeda K., Akira S., Medzhitov R. 2001; Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2:947–950 [View Article][PubMed]
    [Google Scholar]
  58. Sharp F. A., Ruane D., Claass B., Creagh E., Harris J., Malyala P., Singh M., O’Hagan D. T., Pétrilli V. other authors 2009; Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc Natl Acad Sci U S A 106:870–875 [View Article][PubMed]
    [Google Scholar]
  59. Shi Y., HogenEsch H., Hem S. L. 2001; Change in the degree of adsorption of proteins by aluminum-containing adjuvants following exposure to interstitial fluid: freshly prepared and aged model vaccines. Vaccine 20:80–85 [View Article][PubMed]
    [Google Scholar]
  60. Shi Y., Evans J. E., Rock K. L. 2003; Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521 [View Article][PubMed]
    [Google Scholar]
  61. Soehnlein O., Zernecke A., Eriksson E. E., Rothfuchs A. G., Pham C. T., Herwald H., Bidzhekov K., Rottenberg M. E., Weber C., Lindbom L. 2008; Neutrophil secretion products pave the way for inflammatory monocytes. Blood 112:1461–1471 [View Article][PubMed]
    [Google Scholar]
  62. Sokal E. M., Hoppenbrouwers K., Vandermeulen C., Moutschen M., Léonard P., Moreels A., Haumont M., Bollen A., Smets F., Denis M. 2007; Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis 196:1749–1753 [View Article][PubMed]
    [Google Scholar]
  63. Sornasse T., Flamand V., De Becker G., Bazin H., Tielemans F., Thielemans K., Urbain J., Leo O., Moser M. 1992; Antigen-pulsed dendritic cells can efficiently induce an antibody response in vivo . J Exp Med 175:15–21 [View Article][PubMed]
    [Google Scholar]
  64. Steinhagen F., Kinjo T., Bode C., Klinman D. M. 2011; TLR-based immune adjuvants. Vaccine 29:3341–3355 [View Article][PubMed]
    [Google Scholar]
  65. Takeda K., Akira S. 2005; Toll-like receptors in innate immunity. Int Immunol 17:1–14 [View Article][PubMed]
    [Google Scholar]
  66. Tritto E., Mosca F., De Gregorio E. 2009; Mechanism of action of licensed vaccine adjuvants. Vaccine 27:3331–3334 [View Article][PubMed]
    [Google Scholar]
  67. Ueda Y., Cain D. W., Kuraoka M., Kondo M., Kelsoe G. 2009; IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia. J Immunol 182:6477–6484 [View Article][PubMed]
    [Google Scholar]
  68. Vesikari T., Karvonen A., Tilman S., Borkowski A., Montomoli E., Banzhoff A., Clemens R. 2010; Immunogenicity and safety of MF59-adjuvanted H5N1 influenza vaccine from infancy to adolescence. Pediatrics 126:e762–e770 [View Article][PubMed]
    [Google Scholar]
  69. Wang H.-B., Weller P. F. 2008; Pivotal advance: eosinophils mediate early alum adjuvant-elicited B cell priming and IgM production. J Leukoc Biol 83:817–821 [View Article][PubMed]
    [Google Scholar]
  70. Yang C., Shi H., Zhou J., Liang Y., Xu H. 2009; CpG oligodeoxynucleotides are a potent adjuvant for an inactivated polio vaccine produced from Sabin strains of poliovirus. Vaccine 27:6558–6563 [View Article][PubMed]
    [Google Scholar]
  71. Yang C.-W., Strong B. S. I., Miller M. J., Unanue E. R. 2010; Neutrophils influence the level of antigen presentation during the immune response to protein antigens in adjuvants. J Immunol 185:2927–2934 [View Article][PubMed]
    [Google Scholar]
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