Key roles of adjuvants in modern vaccines

Nature Medicine

Volumn 19, Issue 12, 2013, Pages 1597-1608

  Reed, Steven G ^a   Orr, Mark T ^a   Fox, Christopher B ^a  

^a INFECTIOUS DISEASE RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALUMINUM SALT; BCG VACCINE; CPG OLIGODEOXYNUCLEOTIDE; DIPHTHERIA PERTUSSIS TETANUS VACCINE; DOUBLE STRANDED RNA; FLAGELLIN; FREUND ADJUVANT; HEPATITIS A VACCINE; HEPATITIS B ANTIGEN; HEPATITIS B VACCINE; HEPISLAV; IMIQUIMOD; IMMUNOLOGICAL ADJUVANT; INFLUENZA VACCINE; ISCOM; LECTIN; LIPID A; MALARIA VACCINE; MELACINE; MIFAMURTIDE; PHOSPHORYL LIPID A; POLIOMYELITIS VACCINE; POLLINEX QUATTRO; QS 21; RABIES VACCINE; RESIQUIMOD; RTSS; SAPONIN; SINGLE STRANDED RNA; TYPHOID VACCINE; UNCLASSIFIED DRUG; VACCINE; VIROSOME; WART VIRUS VACCINE;

2009 H1N1 INFLUENZA; ADD ON THERAPY; ADJUVANT THERAPY; ANTIBODY RESPONSE; ANTIBODY TITER; ANTIGEN PRESENTATION; CD8+ T LYMPHOCYTE; CELL SURFACE; CELLULAR IMMUNITY; CYTOTOXIC T LYMPHOCYTE; DIPHTHERIA; DNA IMMUNIZATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG FORMULATION; DRUG MECHANISM; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; EMULSION; GENE EXPRESSION; HELPER CELL; HEPATITIS A; HEPATITIS B; HUMAN; HUMORAL IMMUNITY; IMMUNE RESPONSE; IMMUNOGENICITY; INFLUENZA A; INFLUENZA A (H1N1); LEUKOCYTE MIGRATION; LIPOSOMAL DELIVERY; MALARIA; NARCOLEPSY; NATURAL KILLER T CELL; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PERTUSSIS; POLIOMYELITIS; PRIORITY JOURNAL; RABIES; REVIEW; TETANUS; TH1 CELL; TH2 CELL; TUBERCULOSIS; TYPHOID FEVER; VACCINATION; VERRUCA VULGARIS;

EID: 84889770121     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3409     Document Type: Review

References (130)

1. McKee, A.S., Munks, M.W. & Marrack, P. How do adjuvants work Important considerations for new generation adjuvants. Immunity 27, 687-690 (2007). (Pubitemid 350102263)
2. Presidents Council of Advisors on Science and Technology. Report to the President on reengineering the influenza vaccine production enterprise to meet the challenges of pandemic influenza. http://www.whitehouse.gov/sites/default/ files/microsites/ostp/PCAST-Influenza-Vaccinology-Report.pdf (2010).
3. Cox, M. Update on clinical trials evaluation of adjuvanted rHA(H5) vaccines. in 7th WHO Meeting on Evaluation of Pandemic Influenza Vaccines in Clinical Trials (Geneva, Switzerland, 2011).
4. Tong, N.K. et al. Immunogenicity and safety of an adjuvanted hepatitis B vaccine in pre-hemodialysis and hemodialysis patients. Kidney Int. 68, 2298-2303 (2005). (Pubitemid 43117807)
5. Levie, K., Gjorup, I., Skinhoj, P. & Stoffel, M. A 2-dose regimen of a recombinant hepatitis B vaccine with the immune stimulant AS04 compared with the standard 3-dose regimen of Engerix-B in healthy young adults. Scand. J. Infect. Dis. 34, 610-614 (2002). (Pubitemid 35012346)
6. Wiley, S.R. et al. Targeting TLRs expands the antibody repetoire in response to a malaria vaccine. Sci. Transl. Med. 3, 93ra69 (2011).
7. Draper, E. et al. A randomized, observer-blinded immunogenicity trial of Cervarix and Gardasil human papillomavirus vaccines in 12-15 year old girls. PLoS ONE 8, e61825 (2013).
8. Galli, G. et al. Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine. Proc. Natl. Acad. Sci. USA 106, 7962-7967 (2009).
9. Khurana, S. et al. MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines. Sci. Transl. Med. 3, 85ra48 (2011).
10. Kasturi, S.P. et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470, 543-547 (2011).
11. McCluskie, M.J. et al. Enhancing immunogenicity of a 3aminomethylnicotine-DT-conjugate anti-nicotine vaccine with CpG adjuvant in mice and non-human primates. Int. Immunopharmacol. 16, 50-56 (2013).
12. Eng, N.F., Bhardwaj, N., Mulligan, R. & Diaz-Mitoma, F. The potential of 1018 ISS adjuvant in hepatitis B vaccines. Hum. Vaccin. Immunother. 9, 1661-1672 (2013).
13. Agnandji, S.T. et al. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N. Engl. J. Med. 365, 1863-1875 (2011).
14. Fox, C.B., Baldwin, S.L., Duthie, M.S., Reed, S.G. & Vedvick, T.S. Immunomodulatory and physical effects of oil composition in vaccine adjuvant emulsions. Vaccine 29, 9563-9572 (2011).
15. Morel, S. et al. Adjuvant System AS03 containing -tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine 29, 2461-2473 (2011).
16. Mosca, F. et al. Molecular and cellular signatures of human vaccine adjuvants. Proc. Natl. Acad. Sci. USA 105, 10501-10506 (2008).
17. Seubert, A., Monaci, E., Pizza, M., Ohagan, 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).
18. Ohagan, D.T., Ott, G.S., De Gregorio, E. & Seubert, A. The mechanism of action of MF59-an innately attractive adjuvant formulation. Vaccine 30, 4341-4348 (2012).
19. Ellebedy, A.H. et al. Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59. Proc. Natl. Acad. Sci. USA 108, 2927-2932 (2011).
20. 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. USA 108, 11169-11174 (2011).
21. De Gregorio, E., Tritto, E. & Rappuoli, R. Alum adjuvanticity: unraveling a century old mystery. Eur. J. Immunol. 38, 2068-2071 (2008).
22. Mbow, M.L., De Gregorio, E. & Ulmer, J.B. Alums adjuvant action: grease is the word. Nat. Med. 17, 415-416 (2011).
23. Flach, T.L. et al. Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat. Med. 17, 479-487 (2011).
24. Bachmann, M.F. & Jennings, G.T. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat. Rev. Immunol. 10, 787-796 (2010).
25. Hubbell, J.A., Thomas, S.N. & Swartz, M.A. Materials engineering for immunomodulation. Nature 462, 449-460 (2009).
26. Oyewumi, M.O., Kumar, A. & Cui, Z. Nano-microparticles as immune adjuvants: correlating particle sizes and the resultant immune responses. Expert Rev. Vaccines 9, 1095-1107 (2010).
27. Kim, H.M., Uto, T., Akagi, T., Baba, M. & Akashi, M. Amphiphilic poly(amino acid) nanoparticles induce size-dependent dendritic cell maturation. Adv. Funct. Mater. 20, 3925-3931 (2010).
28. Sharma, G. et al. Polymer particle shape independently influences binding and internalization by macrophages. J. Control. Release 147, 408-412 (2010).
29. Teo, B.K.K. et al. The effect of micro and nanotopography on endocytosis in drug and gene delivery systems. Biomaterials 32, 9866-9875 (2011).
30. Chua, B.Y., Al Kobaisi, M., Zeng, W., Mainwaring, D. & Jackson, D.C. Chitosan microparticles and nanoparticles as biocompatible delivery vehicles for peptide and protein-based immunocontraceptive vaccines. Mol. Pharm. 9, 81-90 (2012).
31. Pal, I. & Ramsey, J.D. The role of the lymphatic system in vaccine trafficking and immune response. Adv. Drug Deliv. Rev. 63, 909-922 (2011).
32. Reddy, S.T. et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat. Biotechnol. 25, 1159-1164 (2007). (Pubitemid 47538111)
33. Henriksen-Lacey, M., Devitt, A. & Perrie, Y. The vesicle size of DDA:TDB liposomal adjuvants plays a role in the cell-mediated immune response but has no significant effect on antibody production. J. Control. Release 154, 131-137 (2011).
34. Li, X., Sloat, B.R., Yanasarn, N. & Cui, Z. Relationship between the size of nanoparticles and their adjuvant activity: data from a study with an improved experimental design. Eur. J. Pharm. Biopharm. 78, 107-116 (2011).
35. Alkilany, A.M. & Murphy, C.J. Toxicity and cellular uptake of gold nanoparticles: what we have learned so far J. Nanopart. Res. 12, 2313-2333 (2010).
36. Clapp, T., Siebert, P., Chen, D. & Braun, L.J. Vaccines with aluminum-containing adjuvants: optimizing vaccine efficacy and thermal stability. J. Pharm. Sci. 100, 388-401 (2011).
37. Henriksen-Lacey, M. et al. Liposomal cationic charge and antigen adsorption are important properties for the efficient deposition of antigen at the injection site and ability of the vaccine to induce CMI response. J. Control. Release 145, 102-108 (2010).
38. Watson, D.S., Platt, V.M., Cao, L., Venditto, V.J. & Szoka, F.C. Jr. Antibody response to polyhistidine-tagged peptide and protein antigens attached to liposomes via lipid-linked nitrilotriacetic acid in mice. Clin. Vaccine Immunol. 18, 289-297 (2011).
39. Guan, H.H. et al. Liposomal formulations of synthetic MUC1 peptides: effects of encapsulation versus surface display of peptides on immune responses. Bioconjug. Chem. 9, 451-458 (1998). (Pubitemid 28338759)
40. Shahum, E. & Therien, H.M. Immunopotentiation of the humoral response by liposomes: encapsulation versus covalent linkage. Immunology 65, 315-317 (1988).
41. Yanasarn, N., Sloat, B.R. & Cui, Z. Negatively charged liposomes show potent adjuvant activity when simply admixed with protein antigens. Mol. Pharm. 8, 1174-1185 (2011).
42. Beaudette, T.T. et al. In vivo studies on the effect of co-encapsulation of CpG DNA and antigen in acid-degradable microparticle vaccines. Mol. Pharm. 6, 1160-1169 (2009).
43. Smirnov, D., Schmidt, J.J., Capecchi, J.T. & Wightman, P.D. Vaccine adjuvant activity of 3M-052: an imidazoquinoline designed for local activity without systemic cytokine induction. Vaccine 29, 5434-5442 (2011).
44. Walczyk, D., Bombelli, F.B., Monopoli, M.P., Lynch, I. & Dawson, K.A. What the cell "sees" in bionanoscience. J. Am. Chem. Soc. 132, 5761-5768 (2010).
45. Zhang, H. et al. Quantitative proteomics analysis of adsorbed plasma proteins classifies nanoparticles with different surface properties and size. Proteomics 11, 4569-4577 (2011).
46. Mohanan, D. et al. Administration routes affect the quality of immune responses: A cross-sectional evaluation of particulate antigen-delivery systems. J. Control. Release 147, 342-349 (2010).
47. Slütter, B., Bal, S.M., Ding, Z., Jiskoot, W. & Bouwstra, J.A. Adjuvant effect of cationic liposomes and CpG depends on administration route. J. Control. Release 154, 123-130 (2011).
48. Fox, C.B., Carter, D., Baldwin, S.L. & Reed, S.G. Innovations in emulsion technology. in Emulsion-Based Vaccine Adjuvants (eds. Fox, C.B., Carter, D. & Reed, S.G.) 38-51 (Future Medicine Ltd., London, 2012).
49. Vogelbruch, M. et al. Aluminium-induced granulomas after inaccurate intradermal hyposensitization injections of aluminium-adsorbed depot preparations. Allergy 55, 883-887 (2000). (Pubitemid 30643915)
50. Stoute, J.A. et al. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. N. Engl. J. Med. 336, 86-91 (1997). (Pubitemid 27020884)
51. Mettens, P. et al. Improved T cell responses to Plasmodium falciparum circumsporozoite protein in mice and monkeys induced by a novel formulation of RTS,S vaccine antigen. Vaccine 26, 1072-1082 (2008).
52. Kester, K.E. et al. Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J. Infect. Dis. 200, 337-346 (2009).
53. Polhemus, M.E. et al. Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults in a high malaria transmission area. PLoS ONE 4, e6465 (2009).
54. Stewart, V.A. et al. Pre-clinical evaluation of new adjuvant formulations to improve the immunogenicity of the malaria vaccine RTS,S/AS02A. Vaccine 24, 6483-6492 (2006). (Pubitemid 44511857)
55. Owusu-Agyei, S. et al. Randomized controlled trial of RTS,S/AS02D and RTS,S/AS01E malaria candidate vaccines given according to different schedules in Ghanaian children. PLoS ONE 4, e7302 (2009).
56. The RTS/S Clinical Trials Partnership. A phase 3 trial of RTS,S/AS01 malaria vaccine in african infants. N. Engl. J. Med. 367, 2284-2295 (2012).
57. Leroux-Roels, I. et al. Improved CD4+ T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: A randomized trial. Vaccine 31, 2196-2206 (2013).
58. Giannini, S.L. et al. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine 24, 5937-5949 (2006). (Pubitemid 44080367)
59. 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).
60. Baudner, B.C. et al. MF59 emulsion is an effective delivery system for a synthetic TLR4 agonist (E6020). Pharm. Res. 26, 1477-1485 (2009).
61. Wack, A. et al. Combination adjuvants for the induction of potent, long-lasting antibody and T-cell responses to influenza vaccine in mice. Vaccine 26, 552-561 (2008).
62. Yang, M. et al. MF59 formulated with CpG ODN as a potent adjuvant of recombinant HSP65-MUC1 for inducing anti-MUC1+ tumor immunity in mice. Int. Immunopharmacol. 13, 408-416 (2012).
63. Singh, M. et al. MF59 oil-in-water emulsion in combination with a synthetic TLR4 agonist (E6020) is a potent adjuvant for a combination Meningococcus vaccine. Hum. Vaccin. Immunother. 8, 486-490 (2012).
64. Rümke, H.C. et al. Selection of an adjuvant for seasonal influenza vaccine in elderly people: modelling immunogenicity from a randomized trial. BMC Infect. Dis. 13, 348 (2013).
65. Baldwin, S.L. et al. Increased potency of an inactivated trivalent polio vaccine with oil-in-water emulsions. Vaccine 29, 644-649 (2011).
66. Baldwin, S.L. et al. The importance of adjuvant formulation in the development of a tuberculosis vaccine. J. Immunol. 188, 2189-2197 (2012).
67. Bertholet, S. et al. Optimized subunit vaccine protects against experimental leishmaniasis. Vaccine 27, 7036-7045 (2009).
68. Orr, M.T. et al. Adjuvant formulation structure and composition is critical for the development of an effective vaccine against tuberculosis. J. Control. Release (in the press) (2013).
69. Ohagan, D.T., Ott, G.S., De Gregorio, E. & Seubert, A. The mechanism of action of MF59-an innately attractive adjuvant formulation. Vaccine 30, 4341-4348 (2012).
70. Moser, C., Amacker, M. & Zurbriggen, R. Influenza virosomes as a vaccine adjuvant and carrier system. Expert Rev. Vaccines 10, 437-446 (2011).
71. Marrack, P., McKee, A.S. & Munks, M.W. Towards an understanding of the adjuvant action of aluminium. Nat. Rev. Immunol. 9, 287-293 (2009).
72. Tritto, E., Mosca, F. & De Gregorio, E. Mechanism of action of licensed vaccine adjuvants. Vaccine 27, 3331-3334 (2009).
73. Schweneker, K. et al. The mycobacterial cord factor adjuvant analogue trehalose-6,6-dibehenate (TDB) activates the Nlrp3 inflammasome. Immunobiology 218, 664-673 (2013).
74. Schoenen, H. et al. Cutting edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate. J. Immunol. 184, 2756-2760 (2010).
75. Bowen, W.S. et al. Selective TRIF-dependent signaling by a synthetic Toll-like receptor 4 agonist. Sci. Signal. 5, ra13 (2012).
76. Orr, M.T. et al. MyD88 and TRIF synergistic interaction is required for TH1-cell polarization with a synthetic TLR4 agonist adjuvant. Eur. J. Immunol. 43, 2398-2408 (2013).
77. Querec, T.D. et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat. Immunol. 10, 116-125 (2009).
78. Querec, T. et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J. Exp. Med. 203, 413-424 (2006). (Pubitemid 43290850)
79. Querec, T.D. et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat. Immunol. 10, 116-125 (2009).
80. Nakaya, H.I. et al. Systems biology of vaccination for seasonal influenza in humans. Nat. Immunol. 12, 786-795 (2011).
81. Caproni, E. et al. MF59 and Pam3CSK4 boost adaptive responses to influenza subunit vaccine through an IFN type I-independent mechanism of action. J. Immunol. 188, 3088-3098 (2012).
82. Kwissa, M., Nakaya, H.I., Oluoch, H. & Pulendran, B. Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates. Blood 119, 2044-2055 (2012).
83. Vahey, M.T. et al. Expression of genes associated with immunoproteasome processing of major histocompatibility complex peptides is indicative of protection with adjuvanted RTS,S malaria vaccine. J. Infect. Dis. 201, 580-589 (2010).
84. Barchet, W., Wimmenauer, V., Schlee, M. & Hartmann, G. Accessing the therapeutic potential of immunostimulatory nucleic acids. Curr. Opin. Immunol. 20, 389-395 (2008).
85. Fox, C.B., Friede, M., Reed, S.G. & Ireton, G.C. Synthetic and natural TLR4 agonists as safe and effective vaccine adjuvants. Subcell. Biochem. 53, 303-321 (2010).
86. Hajjar, A.M., Ernst, R.K., Tsai, J.H., Wilson, C.B. & Miller, S.I. Human Toll-like receptor 4 recognizes host-specific LPS modifications. Nat. Immunol. 3, 354-359 (2002). (Pubitemid 34308623)
87. Kawahara, K., Tsukano, H., Watanabe, H., Lindner, B. & Matsuura, M. Modification of the structure and activity of lipid A in Yersinia pestis lipopolysaccharide by growth temperature. Infect. Immun. 70, 4092-4098 (2002). (Pubitemid 34790917)
88. Steeghs, L. et al. Differential activation of human and mouse Toll-like receptor 4 by the adjuvant candidate LpxL1 of Neisseria meningitidis. Infect. Immun. 76, 3801-3807 (2008).
89. Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196-200 (2002). (Pubitemid 34141451)
90. Jurk, M. et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol. 3, 499 (2002). (Pubitemid 34669818)
91. Klinman, D.M., Currie, D., Gursel, I. & Verthelyi, D. Use of CpG oligodeoxynucleotides as immune adjuvants. Immunol. Rev. 199, 201-216 (2004). (Pubitemid 38736773)
92. Leadbetter, E.A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603-607 (2002). (Pubitemid 34406754)
93. Sablan, B.P. et al. Demonstration of safety and enhanced seroprotection against hepatitis B with investigational HBsAg-1018 ISS vaccine compared to a licensed hepatitis B vaccine. Vaccine 30, 2689-2696 (2012).
94. US Food and Drug Administration Center for Biologics Evaluation and Review. Summary Minutes Vaccines and Related Biological Products Advisory Committee. FDA, http://www.fda.gov/downloads/advisorycommittees/ committeesmeetingmaterials/bloodvaccinesandotherbiologics/ vaccinesandrelatedbiologicalproductsadvisorycommittee/ucm333704.pdf (2012).
95. Saade, F. & Petrovsky, N. Technologies for enhanced efficacy of DNA vaccines. Expert Rev. Vaccines 11, 189-209 (2012).
96. Saxena, M., Van, T.T., Baird, F.J., Coloe, P.J. & Smooker, P.M. Pre-existing immunity against vaccine vectors-friend or foe Microbiology 159, 1-11 (2013).
97. Nohynek, H. et al. AS03 adjuvanted H1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS ONE 7, e33536 (2012).
98. Partinen, M. et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS ONE 7, e33723 (2012).
99. European Medicines Agency. European Medicines Agency recommends restricting use of Pandemrix. http://www.ema.europa.eu/docs/en-GB/document- library/Press-release/2011/07/WC500109182.pdf (2011).
100. Heier, M.S. et al. Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. Sleep Med. 14, 867-871 (2013).
101. Szakács, A., Darin, N. & Hallbook, T. Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology 80, 1315-1321 (2013).
102. Miller, E. et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. Br. Med. J. 346, f794 (2013).
103. Morris, K. Implications of narcolepsy link with swine-influenza vaccine. Lancet Infect. Dis. 13, 396-397 (2013).
104. European Medicines Agency. European Medicines Agency reviews hypothesis on Pandemrix and development of narcolepsy. http://www.ema.europa.eu/docs/en-GB/ document-library/Press-release/2012/10/WC500134087.pdf (2012).
105. Tsai, T.F. et al. Explorations of clinical trials and pharmacovigilance databases of MF59-adjuvanted influenza vaccines for associated cases of narcolepsy. Scand. J. Infect. Dis. 43, 702-706 (2011).
106. Han, F. et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann. Neurol. 70, 410-417 (2011).
107. Ueno, H. et al. Targeting human dendritic cell subsets for improved vaccines. Semin. Immunol. 23, 21-27 (2011).
108. Kadowaki, N. et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194, 863-869 (2001). (Pubitemid 32983021)
109. Jongbloed, S.L. et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J. Exp. Med. 207, 1247-1260 (2010).
110. Bachem, A. et al. Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J. Exp. Med. 207, 1273-1281 (2010).
111. Di Pucchio, T. et al. Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I. Nat. Immunol. 9, 551-557 (2008). (Pubitemid 351560524)
112. Jego, G. et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19, 225-234 (2003). (Pubitemid 37011337)
113. Fonteneau, J.F. et al. Activation of influenza virus-specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity. Blood 101, 3520-3526 (2003).
114. Klechevsky, E. et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity 29, 497-510 (2008).
115. Klechevsky, E. et al. Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR. Blood 116, 1685-1697 (2010).
116. Caux, C. et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor : II. Functional analysis. Blood 90, 1458-1470 (1997). (Pubitemid 27355417)
117. Lencer, W.I. & Von Andrian, U.H. Eliciting mucosal immunity. N. Engl. J. Med. 365, 1151-1153 (2011).
118. Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717-723 (2012).
119. 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). (Pubitemid 351549884)
120. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237-241 (2006). (Pubitemid 43372104)
121. Eisenbarth, S.C., Colegio, O.R., Oconnor, 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). (Pubitemid 351871731)
122. Franchi, L. & Nunez, G. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1b secretion but dispensable for adjuvant activity. Eur. J. Immunol. 38, 2085-2089 (2008).
123. 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).
124. 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).
125. 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).
126. Kool, M., Fierens, K. & Lambrecht, B.N. Alum adjuvant: some of the tricks of the oldest adjuvant. J. Med. Microbiol. 61, 927-934 (2012).
127. Marichal, T. et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat. Med. 17, 996-1002 (2011).
128. Shah, H.B., Devera, T.S., Rampuria, P., Lang, G.A. & Lang, M.L. Type II NKT cells facilitate alum-sensing and humoral immunity. J. Leukoc. Biol. 92, 883-893 (2012).
129. 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). (Pubitemid 351959860)
130. Wang, Y., Rahman, D. & Lehner, T. A comparative study of stress-mediated immunological functions with the adjuvanticity of alum. J. Biol. Chem. 287, 17152-17160 (2012).