Abstract
For well over 80 years, alum is the most widely used adjuvant.The use of alternative adjuvants has been explored, however, aluminum adjuvants will continue to be used for many years. This is due to their good track record of safety, low cost, and adjuvanticity with a variety of antigens. Surprisingly, itsmechanism of action remains largely unknown.
In this book chapter we will describe the different alum formulations and our current understandingof its working mechanism, although alum’s final mode of action is not definite yet.
Abstract
Vaccinations have been given for well over a 100 years at the moment. The first reported vaccination was done by Edward Jenner in 1796 [1, 2]. He inoculated a young boy with cowpox virus and thereby rendered him resistant to a subsequent challenge with smallpox virus, an experiment that today would most certainly not be approved by regulatory agencies. Protection by vaccination can be achieved by giving inactivated microbes of virus particles, live attenuated virus, or subunit vaccine. However, subunit vaccination does not induce a strong immune response, which can be achieved by the administration of an adjuvant (Latin verb adjuvare means to help/aid). In immunology, an adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in it.
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References
Hansen, B., Sokolovska, A., HogenEsch, H., Hem, S.L.: Relationship between the strength of antigen adsorption to an aluminum-containing adjuvant and the immune response. Vaccine 25, 6618–6624 (2007)
Jenner, E.: The Three Original Publications on Vaccination Against Smallpox. Harvard Classics. P.F. Collier & Son, New York (1909)
Jiang, D., Morefield, G.L., HogenEsch, H., Hem, S.L.: Relationship of adsorption mechanism of antigens by aluminum-containing adjuvants to in vitro elution in interstitial fluid. Vaccine 24, 1665–1669 (2006)
Glenny, A.: Insoluble precipitates in diphtheria and tetanus immunization. Br. Med. J. 2, 244–245 (1930)
Romero Méndez, I.Z., Shi, Y., HogenEsch, H., Hem, S.L.: Potentiation of the immune response to non-adsorbed antigens by aluminum-containing adjuvants. Vaccine 25, 825–833 (2007)
Tritto, E., Mosca, F., De Gregorio, E.: Mechanism of action of licensed vaccine adjuvants. Vaccine 27, 3331–3334 (2009)
Iyer, S., HogenEsch, H., Hem, S.L.: Effect of the degree of phosphate substitution in aluminum hydroxide adjuvant on the adsorption of phosphorylated proteins. Pharm. Dev. Technol. 8, 81–86 (2003)
Shi, Y., HogenEsch, H., Hem, S.L.: 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 (2001)
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)
Glenny, A., Pope, C., Waddington, H., Wallace, U.: Immunological notes. XVII. The antigenic value of toxoid precipitated by potassium alum. J. Path. and Bact 29, 31–40 (1926)
Heegaard, P.M.H., et al.: Adjuvants and delivery systems in veterinary vaccinology: current state and future developments. Arch. Virol. 156, 183–202 (2011)
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)
Hem, S.L., HogenEsch, H.: Relationship between physical and chemical properties of aluminum-containing adjuvants and immunopotentiation. Expert Rev. Vaccines 6, 685–698 (2007)
Goto, N., Akama, K.: Histopathological studies of reactions in mice injected with aluminum-adsorbed tetanus toxoid. Microbiol. Immunol. 26, 1121–1132 (1982)
Goto, N., et al.: Local tissue irritating effects and adjuvant activities of calcium phosphate and aluminium hydroxide with different physical properties. Vaccine 15, 1364–1371 (1997)
Gupta, R.K., Chang, A.C., Griffin, P., Rivera, R., Siber, G.R.: In vivo distribution of radioactivity in mice after injection of biodegradable polymer microspheres containing 14C-labeled tetanus toxoid. Vaccine 14, 1412–1416 (1996)
Hem, S.L., HogenEsch, H., Middaugh, C.R., Volkin, D.B.: Preformulation studies – the next advance in aluminum adjuvant-containing vaccines. Vaccine 28, 4868–4870 (2010)
Hutchison, S., et al.: Antigen depot is not required for alum adjuvanticity. FASEB J. 26, 1272–1279 (2011)
Noe, S.M., Green, M.A., HogenEsch, H., Hem, S.L.: Mechanism of immunopotentiation by aluminum-containing adjuvants elucidated by the relationship between antigen retention at the inoculation site and the immune response. Vaccine 28, 3588–3594 (2010)
Munks, M.W., et al.: Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo. Blood 116, 5191–5199 (2010)
Lambrecht, B.N., Kool, M., Willart, M.A.M., Hammad, H.: Mechanism of action of clinically approved adjuvants. Curr. Opin. Immunol. 21, 23–29 (2009)
Steinman, R.M., Pope, M.: Exploiting dendritic cells to improve vaccine efficacy. J. Clin. Invest. 109, 1519–1526 (2002)
Pashine, A., Valiante, N.M., Ulmer, J.B.: Targeting the innate immune response with improved vaccine adjuvants. Nat. Med. 11, S63–S68 (2005)
Bendelac, A., Medzhitov, R.: Adjuvants of immunity: harnessing innate immunity to promote adaptive immunity. J. Exp. Med. 195, F19–F23 (2002)
Kool M., et al.: Cutting edge: Alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755–3759 (2008)
Seubert, A., et al.: Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88. Proc. Natl. Acad. Sci. 108, 11169–11174 (2011)
McKee, A.S., et al.: 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 (2009)
Calabro, S., et al.: 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 (2011)
Didierlaurent, A.M., et al.: 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 (2009)
Mosca, F., et al.: Molecular and cellular signatures of human vaccine adjuvants. Proc. Natl. Acad. Sci. 105, 10501–10506 (2008)
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)
Sun, H., Pollock, K.G.J., 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)
Li, H., Nookala, S., Re, F.: Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1beta and IL-18 release. J. Immunol. 178, 5271–5276 (2007)
Marichal, T., et al.: DNA released from dying host cells mediates aluminum adjuvant activity. Nat. Med. 17, 996–1002 (2011)
Langlet, C., et al.: CD64 expression distinguishes monocyte-derived and conventional dendritic cells and reveals their distinct role during intramuscular immunization. J. Immunol. 188, 1751–1760 (2012)
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)
Seubert, A., Monaci, E., Pizza, M., O’Hagan, D.T., Wack, A.: The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells. J. Immunol. 180, 5402–5412 (2008)
Ghimire, T.R., Benson, R.A., Garside, P., Brewer, J.M.: Alum increases antigen uptake, reduces antigen degradation and sustains antigen presentation by DCs in vitro. Immunol. Lett. 147, 55–62 (2012)
Flach, T.L., et al.: Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat. Med. 17, 479–487 (2011)
Burgdorf, S., Kautz, A., Böhnert, V., Knolle, P.A., Kurts, C.: Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science 316, 612–616 (2007)
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)
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)
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)
Wijburg, O.L., et al.: The role of macrophages in the induction and regulation of immunity elicited by exogenous antigens. Eur. J. Immunol. 28, 479–487 (1998)
Bomford, R.: The comparative selectivity of adjuvants for humoral and cell-mediated immunity. II. Effect on delayed-type hypersensitivity in the mouse and guinea pig, and cell-mediated immunity to tumour antigens in the mouse of Freund’s incomplete and complete adjuvants, alhydrogel, Corynebacterium parvum, Bordetella pertussis, muramyl dipeptide and saponin. Clin. Exp. Immunol. 39, 435–441 (1980)
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)
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)
Serre, K., et al.: IL-4 directs both CD4 and CD8 T cells to produce Th2 cytokines in vitro, but only CD4 T cells produce these cytokines in response to alum-precipitated protein in vivo. Mol. Immunol. 47, 1914–1922 (2010)
Gavin, A.L., et al.: Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314, 1936–1938 (2006)
Schnare, M., et al.: Toll-like receptors control activation of adaptive immune responses. Nat. Immunol. 2, 947–950 (2001)
Nemazee, D., Gavin, A., Hoebe, K., Beutler, B.: Immunology: toll-like receptors and antibody responses. Nature 441, (2006)
Palm, N.W., Medzhitov, R.: Immunostimulatory activity of haptenated proteins. Proc. Natl. Acad. Sci. 106, 4782–4787 (2009)
Martinon, F., Tschopp, J.: Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 14, 10–22 (2007)
Ting, J.P.Y., Willingham, S.B., Bergstralh, D.T.: NLRs at the intersection of cell death and immunity. Nat. Rev. Immunol. 8, 372–379 (2008)
Mariathasan, S., Monack, D.M.: Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat. Rev. Immunol. 7, 31–40 (2007)
Martinon, F., Gaide, O., Pétrilli, V., Mayor, A., Tschopp, J.: NALP inflammasomes: a central role in innate immunity. Semin. Immunopathol. 29, 213–229 (2007)
Fritz, J.H., Ferrero, R.L., Philpott, D.J., Girardin, S.E.: Nod-like proteins in immunity, inflammation and disease. Nat. Immunol. 7, 1250–1257 (2006)
Kawai, T., Akira, S.: Signaling to NF-κB by Toll-like receptors. Trends Mol. Med. 13, 460–469 (2007)
Arend, W.P., Palmer, G., Gabay, C.: IL-1, IL-18, and IL-33 families of cytokines. Immunol. Rev. 223, 20–38 (2008)
Kool, M., et al.: Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755–3759 (2008)
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)
Li, H., Willingham, S.B., Ting, J.P.Y., Re, F.: Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J. Immunol. 181, 17–21 (2008)
Franchi, L., Núñez, 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)
Nakashima, K., et al.: A novel Syk kinase-selective inhibitor blocks antigen presentation of immune complexes in dendritic cells. Eur. J. Pharmacol. 505, 223–228 (2004)
Greenberg, S., Chang, P., Wang, D.C., Xavier, R., Seed, B.: Clustered syk tyrosine kinase domains trigger phagocytosis. Proc. Natl. Acad. Sci. U.S.A. 93, 1103–1107 (1996)
Turner, M., Schweighoffer, E., Colucci, F., Di Santo, J.P., Tybulewicz, V.L.: Tyrosine kinase SYK: essential functions for immunoreceptor signalling. Immunol. Today 21, 148–154 (2000)
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)
Kuroda, E., et al. Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms. Immunity. 34, 1–13 (2011)
Kool, M., et al.: 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 (2011)
Mori, A., et al.: The vaccine adjuvant alum inhibits IL-12 by promoting PI3 kinase signaling while chitosan does not inhibit IL-12 and enhances Th1 and Th17 responses. Eur. J. Immunol. 42, 2709–2719 (2012)
Goto, N., Akama, K.: Local histopathological reactions to aluminum-adsorbed tetanus toxoid. Naturwissenschaften 71, 427–428 (1984)
Alving, C.R., Peachman, K.K., Rao, M., Reed, S.G.: Adjuvants for human vaccines. Curr. Opin. Immunol. 24, 310–315 (2012)
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Kool, M., Lambrecht, B.N. (2014). Mechanism of Adjuvanticity of Aluminum-Containing Formulas. In: Giese, M. (eds) Molecular Vaccines. Springer, Cham. https://doi.org/10.1007/978-3-319-00978-0_14
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DOI: https://doi.org/10.1007/978-3-319-00978-0_14
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