Alum: an Old Dog with New Tricks

Overview

Journal Emerg Microbes Infect

Specialty Infectious Diseases

Date 2016 Mar 24

PMID 27004761

Citations 35

Authors

Yumei Wen

Yan Shi

Affiliations

Soon will be listed here.

Abstract

Aluminum compounds (alum) are the most widely used adjuvants in veterinary and human vaccines. Alum was initially thought to be a simple depot for antigen retention; however, our understanding of the mechanism by which it works has progressed substantially in recent decades. Nonetheless, consensus regarding its roles in different aspects of immune regulation has not been reached, and it remains a long-standing research subject in the field of vaccinology. This review, in chronological order, discusses the various hypotheses proposed in mostly inadequate attempts to illuminate the mechanism by which alum works, from the depot theory to the involvement of the NLRP3 inflammasome and from cell death-associated danger factors to crystalline structure-mediated plasma membrane alteration. In addition, novel findings of unexpected beneficial effects of decreased HBV (Hepatitis B virus) viral load and HBeAg seroconversion in chronically infected patients, as well as significant tumor suppression in experimental mice following multiple alum-only injections are examined, revealing alum's potential clinical applications beyond its use as a simple tool in antigen preparation. With increasing threats of emerging microbes, originating from natural or man-made sources, that pose significant health concerns at the population scale, the potential use of alum as a 'first-aid' vaccine is also discussed.

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References

Schnare M, BARTON G, Holt A, Takeda K, Akira S, Medzhitov R . Toll-like receptors control activation of adaptive immune responses. Nat Immunol. 2001; 2(10):947-50. DOI: 10.1038/ni712. View

Hansen B, Sokolovska A, HogenEsch H, Hem S . Relationship between the strength of antigen adsorption to an aluminum-containing adjuvant and the immune response. Vaccine. 2007; 25(36):6618-24. DOI: 10.1016/j.vaccine.2007.06.049. View

Rathinam V, Jiang Z, Waggoner S, Sharma S, Cole L, Waggoner L . The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol. 2010; 11(5):395-402. PMC: 2887480. DOI: 10.1038/ni.1864. View

McKee A, Munks M, MacLeod M, Fleenor C, van Rooijen N, Kappler J . 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. 2009; 183(7):4403-14. PMC: 2912728. DOI: 10.4049/jimmunol.0900164. View

Zhou R, Yazdi A, Menu P, Tschopp J . A role for mitochondria in NLRP3 inflammasome activation. Nature. 2010; 469(7329):221-5. DOI: 10.1038/nature09663. View

Hutchison S, Benson R, Gibson V, Pollock A, Garside P, Brewer J . Antigen depot is not required for alum adjuvanticity. FASEB J. 2011; 26(3):1272-9. PMC: 3289510. DOI: 10.1096/fj.11-184556. View

Watkinson A, Soliakov A, Ganesan A, Hirst K, Lebutt C, Fleetwood K . Increasing the potency of an alhydrogel-formulated anthrax vaccine by minimizing antigen-adjuvant interactions. Clin Vaccine Immunol. 2013; 20(11):1659-68. PMC: 3837781. DOI: 10.1128/CVI.00320-13. View

Gavin A, Hoebe K, Duong B, Ota T, Martin C, Beutler B . Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science. 2006; 314(5807):1936-8. PMC: 1868398. DOI: 10.1126/science.1135299. View

Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith B, Rajendiran T, Nunez G . K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013; 38(6):1142-53. PMC: 3730833. DOI: 10.1016/j.immuni.2013.05.016. View

10.

Wang B, Wang X, Wen Y, Fu J, Wang H, Ma Z . Suppression of established hepatocarcinoma in adjuvant only immunotherapy: alum triggers anti-tumor CD8+ T cell response. Sci Rep. 2015; 5:17695. PMC: 4673419. DOI: 10.1038/srep17695. View

11.

Sutterwala F, Haasken S, Cassel S . Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci. 2014; 1319:82-95. PMC: 4074217. DOI: 10.1111/nyas.12458. View

12.

Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer A . Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A. 2012; 109(28):11282-7. PMC: 3396518. DOI: 10.1073/pnas.1117765109. View

13.

Sanchez Vallecillo M, Minguito de la Escalera M, Aguirre M, Ullio Gamboa G, Palma S, Gonzalez-Cintado L . A liquid crystal of ascorbyl palmitate, used as vaccine platform, provides sustained release of antigen and has intrinsic pro-inflammatory and adjuvant activities which are dependent on MyD88 adaptor protein. J Control Release. 2015; 214:12-22. DOI: 10.1016/j.jconrel.2015.07.008. View

14.

Sun L, Wu J, Du F, Chen X, Chen Z . Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2012; 339(6121):786-91. PMC: 3863629. DOI: 10.1126/science.1232458. View

15.

Davis B, Wen H, Ting J . The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011; 29:707-35. PMC: 4067317. DOI: 10.1146/annurev-immunol-031210-101405. View

16.

Xu D, Wang X, Shen X, Gong G, Ren H, Guo L . Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings. J Hepatol. 2013; 59(3):450-6. DOI: 10.1016/j.jhep.2013.05.003. View

17.

Eisenbarth S, Colegio O, OConnor W, Sutterwala F, Flavell R . Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008; 453(7198):1122-6. PMC: 4804622. DOI: 10.1038/nature06939. View

18.

Andreakos E, Williams R, Wales J, Foxwell B, Feldmann M . Activation of NF-kappaB by the intracellular expression of NF-kappaB-inducing kinase acts as a powerful vaccine adjuvant. Proc Natl Acad Sci U S A. 2006; 103(39):14459-64. PMC: 1599984. DOI: 10.1073/pnas.0603493103. View

19.

Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K . DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med. 2011; 17(8):996-1002. DOI: 10.1038/nm.2403. View

20.

Rimaniol A, Gras G, Verdier F, Capel F, Grigoriev V, Porcheray F . Aluminum hydroxide adjuvant induces macrophage differentiation towards a specialized antigen-presenting cell type. Vaccine. 2004; 22(23-24):3127-35. DOI: 10.1016/j.vaccine.2004.01.061. View