Adjuvants: Classification, Modus Operandi, and Licensing

Journal of Immunology Research

Volumn 2016, Issue , 2016, Pages

  Apostólico, Juliana De Souza ^a   Lunardelli, Victória Alves Santos ^a   Coirada, Fernanda Caroline ^a   Boscardin, Silvia Beatriz ^b   Rosa, Daniela Santoro ^a,c  

^a FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

^b UNIVERSITY OF SÃO PAULO   (Brazil)

^c Instituto de Investigacao em Imunologia   (Brazil)

Author keywords

[No Author keywords available]

Indexed keywords

AS 01; AS 02; AS 03; AS 04; BACTERIAL TOXIN; FREUND ADJUVANT; IMMUNOLOGICAL ADJUVANT; INCOMPLEYE FREUND ADJUVANT; MIFAMURTIDE; N ACETYLMURAMYLALANYL DEXTRO ISOGLUTAMINE; POLYGLACTIN; POLYLACTIC ACID; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR 5; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; TOLL LIKE RECEPTOR 9; TOLL LIKE RECEPTOR AGONIST; UNCLASSIFIED DRUG; VIROSOME; IMMUNOGLOBULIN RECEPTOR; SUBUNIT VACCINE;

ADVERSE OUTCOME; CLASSIFICATION; CLINICAL TRIAL (TOPIC); DRUG DELIVERY SYSTEM; EMULSION; GOOD MANUFACTURING PRACTICE; HUMAN; IMMUNE RESPONSE; IMMUNOGENICITY; LICENSING; NONHUMAN; PATIENT SAFETY; PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; VACCINATION; VIRUS LIKE AGENT; ANIMAL; CYTOLOGY; HISTORY; IMMUNE SYSTEM; IMMUNOLOGY; METABOLISM; MUCOSAL IMMUNITY;

ADJUVANTS, IMMUNOLOGIC; ANIMALS; HISTORY, 20TH CENTURY; HISTORY, 21ST CENTURY; HUMANS; IMMUNE SYSTEM; IMMUNITY, MUCOSAL; LICENSURE; RECEPTORS, IMMUNOLOGIC; VACCINATION; VACCINES, SUBUNIT;

EID: 84971223738     PISSN: 23148861     EISSN: 23147156     Source Type: Journal    
DOI: 10.1155/2016/1459394     Document Type: Review

References (171)

1. J. C. Cox and A. R. Coulter, "Adjuvants-a classification and review of theirmodes of action, " Vaccine, vol. 15, no. 3, pp. 248-256, 1997.
2. G. Ramon, "Sur la toxine et sur I'anatoxine diphtheriques, " Annales de l'Institut Pasteur, vol. 38, pp. 1-10, 1924.
3. A. D. Pasquale, S. Preiss, F. Silva, and N. Garçon, "Vaccine adjuvants: from 1920 to 2015 and beyond, " Vaccines, vol. 3, no. 2, pp. 320-343, 2015.
4. A. T. Glenny, C. G. Pope, H. Waddington, and U. Wallace, "Immunological notes. XVII-XXIV, " The Journal of Pathology and Bacteriology, vol. 29, no. 1, pp. 31-40, 1926.
5. E. L. Opie, "An experimental study of protective inoculation with heat killed tubercle bacilli, " The Journal of Experimental Medicine, vol. 66, no. 6, pp. 761-788, 1937.
6. B. Guy, "The perfect mix: recent progress in adjuvant research, " Nature Reviews Microbiology, vol. 5, no. 7, pp. 505-517, 2007.
7. S. Awate, L. A. Babiuk, and G. Mutwiri, "Mechanisms of action of adjuvants, " Frontiers in Immunology, vol. 4, article 114, 2013.
8. S. G. Reed, M. T. Orr, and C. B. Fox, "Key roles of adjuvants in modern vaccines, " Nature Medicine, vol. 19, no. 12, pp. 1597-1608, 2013.
9. R. L. Coffman, A. Sher, and R. A. Seder, "Vaccine adjuvants: putting innate immunity to work, " Immunity, vol. 33, no. 4, pp. 492-503, 2010.
10. M. Singh and D. T. O'Hagan, "Recent advances in vaccine adjuvants, " Pharmaceutical Research, vol. 19, no. 6, pp. 715-728, 2002.
11. A. Pashine, N. M. Valiante, and J. B. Ulmer, "Targeting the innate immune response with improved vaccine adjuvants, " Nature Medicine, vol. 11, no. 4, pp. S63-S68, 2005.
12. N. Goto and K. Akama, "Histopathological studies of reactions in mice injected with aluminum-adsorbed tetanus toxoid, " Microbiology and Immunology, vol. 26, no. 12, pp. 1121-1132, 1982.
13. C. Olive, "Pattern recognition receptors: sentinels in innate immunity and targets of new vaccine adjuvants, " Expert Review of Vaccines, vol. 11, no. 2, pp. 237-256, 2012.
14. E. B. Lindblad, "Aluminium compounds for use in vaccines, " Immunology and Cell Biology, vol. 82, no. 5, pp. 497-505, 2004.
15. R. K. Gupta, B. E. Rost, E. Relyveld, and G. R. Siber, "Adjuvant properties of aluminum and calcium compounds, " Pharmaceutical Biotechnology, vol. 6, pp. 229-248, 1995.
16. V. E. Schijns, "Immunological concepts of vaccine adjuvant activity, " Current Opinion in Immunology, vol. 12, no. 4, pp. 456-463, 2000.
17. S. Hutchison, R. A. Benson, V. B. Gibson, A. H. Pollock, P. Garside, and J. M. Brewer, "Antigen depot is not required for alum adjuvanticity, " The FASEB Journal, vol. 26, no. 3, pp. 1272-1279, 2012.
18. B. N. Lambrecht, M. Kool, M. A. M. Willart, and H. Hammad, "Mechanism of action of clinically approved adjuvants, " Current Opinion in Immunology, vol. 21, no. 1, pp. 23-29, 2009.
19. P. Marrack, A. S. McKee, and M. W. Munks, "Towards an understanding of the adjuvant action of aluminium, " Nature Reviews Immunology, vol. 9, no. 4, pp. 287-293, 2009.
20. M. Kool, T. Soullié, M. Van Nimwegen et al., "Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells, " The Journal of Experimental Medicine, vol. 205, no. 4, pp. 869-882, 2008.
21. S. C. Eisenbarth, O. R. Colegio, W. O'Connor Jr., F. S. Sutterwala, and R. A. Flavell, "Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants, " Nature, vol. 453, no. 7198, pp. 1122-1126, 2008.
22. T. R. Ghimire, R. A. Benson, P. Garside, and J. M. Brewer, "Alum increases antigen uptake, reduces antigen degradation and sustains antigen presentation by DCs in vitro, " Immunology Letters, vol. 147, no. 1-2, pp. 55-62, 2012.
23. A. K. Bajaj, S. C. Gupta, R. K. Pandey, K. Misra, S. Rastogi, and A. K. Chatterji, "Aluminium contact sensitivity, " Contact Dermatitis, vol. 37, no. 6, pp. 307-308, 1997.
24. A. Billiau and P. Matthys, "Modes of action of Freund's adjuvants in experimental models of autoimmune diseases, " Journal of Leukocyte Biology, vol. 70, no. 6, pp. 849-860, 2001.
25. P. P. Leenaars, C. F. Hendriksen, W. A. de Leeuw et al., "The production of polyclonal antibodies in laboratory animals. The report and recommendations of ECVAM workshop 35, " Alternatives to Laboratory Animals, vol. 27, no. 1, pp. 79-102, 1999.
26. CCAC, Guidelines on Antibody Production, Canadian Council on Animal Care, 2002.
27. J. E. Salk and A. M. Laurent, "The use of adjuvants in studies on influenza immunization. I. Measurements in monkeys of the dimensions of antigenicity of virus-mineral oil emulsions, " The Journal of Experimental Medicine, vol. 95, no. 5, pp. 429-447, 1952.
28. A. Mussener, L. Klareskog, J. C. Lorentzen, and S. Kleinau, "TNF dominates cytokine mRNA expression in lymphoid tissues of rats developing collagen-and oil-induced arthritis, " Scandinavian Journal of Immunology, vol. 42, no. 1, pp. 128-134, 1995.
29. L. H. Miller, A. Saul, and S. Mahanty, "Revisiting Freund's incomplete adjuvant for vaccines in the developing world, " Trends in Parasitology, vol. 21, no. 9, pp. 412-414, 2005.
30. D. T. O'Hagan, A. Wack, and A. Podda, "MF59 is a safe and potent vaccine adjuvant for flu vaccines in humans: what did we learn during its development" Clinical Pharmacology and Therapeutics, vol. 82, no. 6, pp. 740-744, 2007.
31. T. Vesikari, M. Pellegrini, A. Karvonen et al., "Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant, " Pediatric Infectious Disease Journal, vol. 28, no. 7, pp. 563-571, 2009.
32. D. T. O'Hagan, G. S. Ott, G. Van Nest, R. Rappuoli, and G. Del Giudice, "The history of MF59- adjuvant: A phoenix that arose from the ashes, " Expert Review of Vaccines, vol. 12, no. 1, pp. 13-30, 2013.
33. T. Vesikari, M. Knuf, P. Wutzler et al., "Oil-in-water emulsion adjuvant with influenza vaccine in young children, " The New England Journal ofMedicine, vol. 365, no. 15, pp. 1406-1416, 2011.
34. H. I. Nakaya, E. Clutterbuck, D. Kazmin et al., "Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood, " Proceedings of the National Academy of Sciences, vol. 113, no. 7, pp. 1853-1858, 2016.
35. T. C. Heineman, M. L. Clements-Mann, G. A. Poland et al., "A randomized, controlled study in adults of the immunogenicity of a novel hepatitis B vaccine containing MF59 adjuvant, " Vaccine, vol. 17, no. 22, pp. 2769-2778, 1999.
36. M. Dupuis, D. M. McDonald, and G. Ott, "Distribution of adjuvant MF59 and antigen gD2 after intramuscular injection in mice, " Vaccine, vol. 18, no. 5-6, pp. 434-439, 1999.
37. I. Stephenson, R. Bugarini, K. G. Nicholson et al., "Crossreactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: A potential priming strategy, " Journal of Infectious Diseases, vol. 191, no. 8, pp. 1210-1215, 2005.
38. A. Seubert, E. Monaci, M. Pizza, D. T. O'hagan, and A. Wack, "The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells, "The Journal of Immunology, vol. 180, no. 8, pp. 5402-5412, 2008.
39. E. De Gregorio, E. Caproni, and J. B. Ulmer, "Vaccine adjuvants: mode of action, " Frontiers in Immunology, vol. 4, article 214, 2013.
40. F. Mosca, E. Tritto, A. Muzzi et al., "Molecular and cellular signatures of human vaccine adjuvants, " Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 30, pp. 10501-10506, 2008.
41. M. Vono, M. Taccone, P. Caccin et al., "The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination, " Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 52, pp. 21095-21100, 2013.
42. N. Garçon, D. W. Vaughn, and A. M. Didierlaurent, "Development and evaluation of AS03, an adjuvant system containing tocopherol and squalene in an oil-in-water emulsion, " Expert Review of Vaccines, vol. 11, no. 3, pp. 349-366, 2012.
43. S. Morel, A. Didierlaurent, P. Bourguignon et al., "Adjuvant system AS03 containing tocopherol modulates innate immune response and leads to improved adaptive immunity, " Vaccine, vol. 29, no. 13, pp. 2461-2473, 2011.
44. J. A. Stoute, M. Slaoui, D. G. Heppner et al., "A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria, " The New England Journal of Medicine, vol. 336, no. 2, pp. 86-91, 1997.
45. J. Díez-Domingo, M. Garcés-Sanchez, J.-M. Baldó et al., "Immunogenicity and safety of H5N1 A/vietnam/1194/2004 (clade 1) AS03-adjuvanted prepandemic candidate influenza vaccines in children aged 3 to 9 years: A phase II, randomized, open, controlled study, " Pediatric Infectious Disease Journal, vol. 29, no. 6, pp. e35-e46, 2010.
46. A. C. Martinez, I. S. De La Cueva, P. Boutet, C. V. Abeele, I. Smolenov, and J.-M. Devaster, "A phase 1, open-label safety and immunogenicity study of an AS03-adjuvanted trivalent inactivated influenza vaccine in children aged 6 to 35 months, " Human Vaccines and Immunotherapeutics, vol. 10, no. 7, pp. 1959-1968, 2014.
47. C. Muratori, R. Bona, and M. Federico, "Lentivirus-based viruslike particles as a new protein delivery tool, " Methods in Molecular Biology, vol. 614, pp. 111-124, 2010.
48. C. Huret, D. Desjardins, M. Miyalou et al., "Recombinant retrovirus-derived virus-like particle-based vaccines induce hepatitis C virus-specific cellular and neutralizing immune responses in mice, " Vaccine, vol. 31, no. 11, pp. 1540-1547, 2013.
49. N. Kushnir, S. J. Streatfield, and V. Yusibov, "Virus-like particles as a highly efficient vaccine platform: diversity of targets and production systems and advances in clinical development, " Vaccine, vol. 31, no. 1, pp. 58-83, 2012.
50. L. Zhang, D. Pasquale, M. Le, R. Patel, and S. Mehdi, "Isolated splenic metastasis in a patient with two distinct genitourinary malignancies, " Journal of Community and Supportive Oncology, vol. 13, no. 6, pp. 229-230, 2015.
51. C. M. Bosio, B. D. Moore, K. L. Warfield et al., "Ebola and Marburg virus-like particles activate human myeloid dendritic cells, " Virology, vol. 326, no. 2, pp. 280-287, 2004.
52. D. M. Da Silva, S. C. Fausch, J. S. Verbeek, and W. M. Kast, "Uptake of human papillomavirus virus-like particles by dendritic cells is mediated by Fc receptors and contributes to acquisition of T cell immunity, "The Journal of Immunology, vol. 178, no. 12, pp. 7587-7597, 2007.
53. C. Dalba, B. Bellier, N. Kasahara, and D. Klatzmann, "Replication-competent vectors and empty virus-like particles: new retroviral vector designs for cancer gene therapy or vaccines, " MolecularTherapy, vol. 15, no. 3, pp. 457-466, 2007.
54. D. M. Smith, J. K. Simon, and J. R. Baker Jr., "Applications of nanotechnology forimmunology, "Nature Reviews Immunology, vol. 13, no. 8, pp. 592-605, 2013.
55. L. Buonaguro, L. Racioppi, M. L. Tornesello et al., "Induction of neutralizing antibodies and cytotoxic T lymphocytes in Balb/c mice immunized with virus-like particles presenting a gp120 molecule from a HIV-1 isolate of clade A, " Antiviral Research, vol. 54, no. 3, pp. 189-201, 2002.
56. R. Zurbriggen, "Immunostimulating reconstituted influenza virosomes, " Vaccine, vol. 21, no. 9-10, pp. 921-924, 2003.
57. M. J. Copland, T. Rades, N. M. Davies, and M. A. Baird, "Lipid based particulate formulations for the delivery of antigen, " Immunology and Cell Biology, vol. 83, no. 2, pp. 97-105, 2005.
58. M. A. Morse, R. Chapman, J. Powderly et al., "Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with toll-like receptor stimulation to induce immunity to selfantigens in cancer patients, " Clinical Cancer Research, vol. 17, no. 14, pp. 4844-4853, 2011.
59. D. Felnerova, J.-F. Viret, R. Glück, and C. Moser, "Liposomes and virosomes as delivery systems for antigens, nucleic acids and drugs, " Current Opinion in Biotechnology, vol. 15, no. 6, pp. 518-529, 2004.
60. P. Elamanchili, C. M. E. Lutsiak, S. Hamdy, M. Diwan, and J. Samuel, "'Pathogen-mimicking' nanoparticles for vaccine delivery to dendritic cells, " Journal of Immunotherapy, vol. 30, no. 4, pp. 378-395, 2007.
61. F. Danhier, E. Ansorena, J. M. Silva, R. Coco, A. Le Breton, and V. Préat, "PLGA-based nanoparticles: An overview of biomedical applications, " Journal of Controlled Release, vol. 161, no. 2, pp. 505-522, 2012.
62. L. J. Cruz, P. J. Tacken, R. Fokkink et al., "Targeted PLGA nanobut not microparticles specifically deliver antigen to human dendritic cells via DC-SIGN in vitro, " Journal of Controlled Release, vol. 144, no. 2, pp. 118-126, 2010.
63. E. MacHo Fernandez, J. Chang, J. Fontaine et al., "Activation of invariant Natural Killer T lymphocytes in response to the galactosylceramide analogue KRN7000 encapsulated in PLGAbased nanoparticles and microparticles, " International Journal of Pharmaceutics, vol. 423, no. 1, pp. 45-54, 2012.
64. J. K. Vasir and V. Labhasetwar, "Biodegradable nanoparticles for cytosolic delivery of therapeutics, " Advanced Drug Delivery Reviews, vol. 59, no. 8, pp. 718-728, 2007.
65. H. Shen, A. L. Ackerman, V. Cody et al., "Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles, " Immunology, vol. 117, no. 1, pp. 78-88, 2006.
66. T. T. Beaudette, E. M. Bachelder, J. A. Cohen et al., "In vivo studies on the effect of co-encapsulation of CpG DNA and antigen in acid-degradable microparticle vaccines, " Molecular Pharmaceutics, vol. 6, no. 4, pp. 1160-1169, 2009.
67. S. de Jong, G. Chikh, L. Sekirov et al., "Encapsulation in liposomal nanoparticles enhances the immunostimulatory, adjuvant and anti-tumor activity of subcutaneously administered CpG ODN, " Cancer Immunology, Immunotherapy, vol. 56, no. 8, pp. 1251-1264, 2007.
68. M. Manish, A. Rahi, M. Kaur, R. Bhatnagar, and S. Singh, "A single-dose PLGA encapsulated protective antigen domain 4 nanoformulation protects mice against Bacillus anthracis spore challenge, " PLoS ONE, vol. 8, no. 4, Article ID e61885, 2013.
69. J. J. Moon, H. Suh, M. E. Polhemus, C. F. Ockenhouse, A. Yadava, and D. J. Irvine, "Antigen-displaying lipid-enveloped PLGA nanoparticles as delivery agents for a Plasmodium vivax malaria vaccine, " PLoSONE, vol. 7, no. 2, Article IDe31472, 2012.
70. C. Thomas, A. Rawat, L. Hope-Weeks, and F. Ahsan, "Aerosolized PLA and PLGA nanoparticles enhance humoral, mucosal and cytokine responses to hepatitis B vaccine, " Molecular Pharmaceutics, vol. 8, no. 2, pp. 405-415, 2011.
71. L. Alexopoulou, A. C. Holt, R. Medzhitov, and R. A. Flavell, "Recognition of double-stranded RNA and activation of NF B by Toll-like receptor 3, " Nature, vol. 413, no. 6857, pp. 732-738, 2001.
72. M. S. Duthie, H. P. Windish, C. B. Fox, and S. G. Reed, "Use of defined TLR ligands as adjuvants within human vaccines, " Immunological Reviews, vol. 239, no. 1, pp. 178-196, 2011.
73. H. Kato, O. Takeuchi, S. Sato et al., "Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses, " Nature, vol. 441, no. 1, pp. 101-105, 2006.
74. M. P. Longhi, C. Trumpfheller, J. Idoyaga et al., "Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant, " The Journal of ExperimentalMedicine, vol. 206, no. 7, pp. 1589-1602, 2009.
75. G. M. Davey, M. Wojtasiak, A. I. Proietto, F. R. Carbone, W. R. Heath, and S. Bedoui, "Cutting edge: priming of CD8 T cell immunity to herpes simplex virus type 1 requires cognate TLR3 expression in vivo, " Journal of Immunology, vol. 184, no. 5, pp. 2243-2246, 2010.
76. O. Schulz, S. S. Diebold, M. Chen et al., "Toll-like receptor 3 promotes cross-priming to virus-infected cells, " Nature, vol. 433, no. 7028, pp. 887-892, 2005.
77. C. Trumpfheller, M. Caskey, G. Nchinda et al., "The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine, " Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 7, pp. 2574-2579, 2008.
78. J. S. Apostólico, S. B. Boscardin, M. M. Yamamoto et al., "HIV envelope trimer specific immune response is influenced by different adjuvant formulations and heterologous prime-boost, " PLOS ONE, vol. 11, no. 1, Article ID e0145637, 2016.
79. H. R. Henriques, E. V. Rampazo, A. J. S. Gonçalves et al., "Targeting the non-structural protein 1 from dengue virus to a dendritic cell population confers protective immunity to lethal virus challenge, " PLoS Neglected Tropical Diseases, vol. 7, no. 7, article e2330, 2013.
80. K. Tewari, B. J. Flynn, S. B. Boscardin et al., "Poly(I:C) is an effective adjuvant for antibody and multi-functional CD4+ T cell responses to Plasmodium falciparum circumsporozoite protein (CSP) and DEC-CSP in non human primates, " Vaccine, vol. 28, no. 45, pp. 7256-7266, 2010.
81. G. Forte, A. Rega, S. Morello et al., "Polyinosinic-polycytidylic acid limits tumor outgrowth in a mouse model of metastatic lung cancer, " The Journal of Immunology, vol. 188, no. 11, pp. 5357-5364, 2012.
82. T. Nagato, Y.-R. Lee, Y. Harabuchi, and E. Celis, "Combinatorial immunotherapy of polyinosinic-polycytidylic acid and blockade of programmed death-ligand 1 induce effective CD8 t-cell responses against established tumors, " Clinical Cancer Research, vol. 20, no. 5, pp. 1223-1234, 2014.
83. C. Stahl-Hennig, M. Eisenblätter, E. Jasny et al., "Synthetic double-stranded RNAs are adjuvants for the induction of T helper 1 and humoral immune responses to human papillomavirus in rhesus macaques, " PLoS Pathogens, vol. 5, no. 4, Article ID e1000373, 2009.
84. D. Ruane, Y. Do, L. Brane et al., "A dendritic cell targeted vaccine induces long-termHIV-specific immunity within the gastrointestinal tract, " Mucosal Immunology, 2016.
85. V. Mata-Haro, C. Cekic, M. Martin, P. M. Chilton, C. R. Casella, and T. C. Mitchell, "The vaccine adjuvantmonophosphoryl lipid A as a TRIF-biased agonist of TLR4, " Science, vol. 316, no. 5831, pp. 1628-1632, 2007.
86. M. Hopkins, B. G. Lees, D. G. Richardson, S. R. Woroniecki, and A. W. Wheeler, "Standardisation of glutaraldehyde-modified tyrosine-adsorbed tree pollen vaccines containing the Th1-inducing adjuvant, monophosphoryl lipid A (MPL), " Allergologia et Immunopathologia, vol. 29, no. 6, pp. 245-254, 2001.
87. M. S. Mitchell, "Perspective on allogeneic melanoma lysates in active specific immunotherapy, " Seminars in Oncology, vol. 25, no. 6, pp. 623-635, 1998.
88. A. M. Didierlaurent, S. Morel, L. Lockman et al., "AS04, an aluminum salt-and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity, " The Journal of Immunology, vol. 183, no. 10, pp. 6186-6197, 2009.
89. J. W. Huleatt, A. R. Jacobs, J. Tang et al., "Vaccination with recombinant fusion proteins incorporating Toll-like receptor ligands induces rapid cellular and humoral immunity, " Vaccine, vol. 25, no. 4, pp. 763-775, 2007.
90. J. Garaude, A. Kent, N. van Rooijen, and J. M. Blander, "Simultaneous targeting of toll-and nod-like receptors induces effective tumor-specific immune responses, " Science Translational Medicine, vol. 4, no. 120, Article ID 120ra16, 2012.
91. Y. Zhao, J. Yang, J. Shi et al., "The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus, " Nature, vol. 477, no. 7366, pp. 596-600, 2011.
92. M. Matusiak, N. VanOpdenbosch, L. VandeWalle, J.-C. Sirard, D.-T. Kanneganti, and M. Lamkanfi, "Flagellin-inducedNLRC4 phosphorylation primes the inflammasome for activation by NAIP5, " Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 5, pp. 1541-1546, 2015.
93. E. M. Kofoed and R. E. Vance, "Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity, " Nature, vol. 477, no. 7366, pp. 592-597, 2011.
94. C. B. Turley, R. E. Rupp, C. Johnson et al., "Safety and immunogenicity of a recombinant M2e-flagellin influenza vaccine (STF2. 4xM2e) in healthy adults, " Vaccine, vol. 29, no. 32, pp. 5145-5152, 2011.
95. D. N. Taylor, J. J. Treanor, E. A. Sheldon et al., "Development of VAX128, a recombinant hemagglutinin (HA) influenza-flagellin fusion vaccine with improved safety and immune response, " Vaccine, vol. 30, no. 39, pp. 5761-5769, 2012.
96. E. H. Kim, J. H. Kim, R. Samivel et al., "Intralymphatic treatment of flagellin-ovalbumin mixture reduced allergic inflammation in murine model of allergic rhinitis, " Allergy, 2016.
97. R. D. Weeratna, S. R. Makinen, M. J. McCluskie, and H. L. Davis, "TLR agonists as vaccine adjuvants: comparison of CpG ODN and Resiquimod (R-848), " Vaccine, vol. 23, no. 45, pp. 5263-5270, 2005.
98. D. I. Bernstein, C. J. Harrison, M. A. Tomai, and R. L. Miller, "Daily or weekly therapy with resiquimod (R-848) reduces genital recurrences in herpes simplex virus-infected guinea pigs during and after treatment, " Journal of Infectious Diseases, vol. 183, no. 6, pp. 844-849, 2001.
99. C. J. Harrison, R. L. Miller, and D. I. Bernstein, "Posttherapy suppression of genital herpes simplex virus (HSV) recurrences and enhancement of HSV-specific T-cell memory by imiquimod in guinea pigs, " Antimicrobial Agents and Chemotherapy, vol. 38, no. 9, pp. 2059-2064, 1994.
100. H. Hemmi, T. Kaisho, K. Takeda, and S. Akira, "The roles of tolllike receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets, "The Journal of Immunology, vol. 170, no. 6, pp. 3059-3064, 2003.
101. S. Akira and K. Takeda, "Toll-like receptor signalling, " Nature Reviews Immunology, vol. 4, no. 7, pp. 499-511, 2004.
102. N. M. Shukla, S. S. Malladi, C. A. Mutz, R. Balakrishna, and S. A. David, "Structure-activity relationships in human tolllike receptor 7-active imidazoquinoline analogues, " Journal of Medicinal Chemistry, vol. 53, no. 11, pp. 4450-4465, 2010.
103. S. Gnjatic, N. B. Sawhney, and N. Bhardwaj, "Toll-like receptor agonists are they good adjuvants" Cancer Journal, vol. 16, no. 4, pp. 382-391, 2010.
104. A. Iwasaki and R. Medzhitov, "Toll-like receptor control of the adaptive immune responses, " Nature Immunology, vol. 5, no. 10, pp. 987-995, 2004.
105. M. Jurk, F. Heil, J. Vollmer et al., "Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848, " Nature Immunology, vol. 3, no. 6, article 499, 2002.
106. K. Loré, M. R. Betts, J. M. Brenchley et al., "Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirusand HIV-1-specific T cell responses, " The Journal of Immunology, vol. 171, no. 8, pp. 4320-4328, 2003.
107. A. Le Bon, N. Etchart, C. Rossmann et al., "Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon, " Nature Immunology, vol. 4, no. 10, pp. 1009-1015, 2003.
108. C. Liu, Y. Lou, G. Lizée et al., "Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell crosspriming and tumor regression in mice, " The Journal of Clinical Investigation, vol. 118, no. 3, pp. 1165-1175, 2008.
109. G. A. Bishop, L. M. Ramirez, M. Baccam, L. K. Busch, L. K. Pederson, and M. A. Tomai, "The immune response modifier resiquimod mimics CD40-induced B cell activation, " Cellular Immunology, vol. 208, no. 1, pp. 9-17, 2001.
110. C. V. Caperton and B. Berman, "Safety, efficacy, and patient acceptability of imiquimod for topical treatment of actinic keratoses, " Clinical, Cosmetic and Investigational Dermatology, vol. 4, pp. 35-40, 2011.
111. V. Oldfield, G. M. Keating, and C. M. Perry, "Imiquimod: in superficial basal cell carcinoma, " American Journal of Clinical Dermatology, vol. 6, no. 3, pp. 195-202, 2005.
112. G. Micali, F. Lacarrubba, M. R. Nasca, S. Ferraro, and R. A. Schwartz, "Topical pharmacotherapy for skin cancer: part II. Clinical applications, " Journal of the American Academy of Dermatology, vol. 70, no. 6, pp. 979. e1-979. e12, 2014.
113. U. R. Hengge, S. Esser, T. Schultewolter et al., "Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum, " British Journal of Dermatology, vol. 143, no. 5, pp. 1026-1031, 2000.
114. T. Rosen, A. Nelson, and K. Ault, "Imiquimod cream 2. 5% and 3. 75% applied once daily to treat external genital warts in men, " Cutis, vol. 96, no. 4, pp. 277-282, 2015.
115. K. E. Mark, L. Corey, T.-C. Meng et al., "Topical resiquimod 0. 01% gel decreases herpes simplex virus type 2 genital shedding: A randomized, controlled trial, " Journal of Infectious Diseases, vol. 195, no. 9, pp. 1324-1331, 2007.
116. K. H. Fife, T.-C. Meng, D. G. Ferris, and P. Liu, "Effect of resiquimod 0. 01% gel on lesion healing and viral sheddingwhen applied to genital herpes lesions, " Antimicrobial Agents and Chemotherapy, vol. 52, no. 2, pp. 477-482, 2008.
117. D. H. Dockrell and G. R. Kinghorn, "Imiquimod and resiquimod as novel immunomodulators, " Journal of Antimicrobial Chemotherapy, vol. 48, no. 6, pp. 751-755, 2001.
118. R. M. Prins, N. Craft, K. W. Bruhn et al., "The TLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: relation to central nervous system antitumor immunity, " The Journal of Immunology, vol. 176, no. 1, pp. 157-164, 2006.
119. D. Smirnov, J. J. Schmidt, J. T. Capecchi, and P. D. Wightman, "Vaccine adjuvant activity of 3m-052: An imidazoquinoline designed for local activity without systemic cytokine induction, " Vaccine, vol. 29, no. 33, pp. 5434-5442, 2011.
120. D. J. Dowling, Z. Tan, Z. M. Prokopowicz et al., "The ultrapotent and selective TLR8 agonist VTX-294 activates human newborn and adult leukocytes, " PLoS ONE, vol. 8, no. 3, Article ID e58164, 2013.
121. C. C. N. Wu, B. Crain, S. Yao et al., "Innate immune protection against infectious diseases by pulmonary administration of a phospholipid-conjugated TLR7 ligand, " Journal of Innate Immunity, vol. 6, no. 3, pp. 315-324, 2014.
122. P. Dasari, I. C. Nicholson, G. Hodge, G. W. Dandie, and H. Zola, "Expression of toll-like receptors on B lymphocytes, " Cellular Immunology, vol. 236, no. 1-2, pp. 140-145, 2005.
123. L. A. J. O'Neill, C. E. Bryant, and S. L. Doyle, "Therapeutic targeting of toll-like receptors for infectious and inflammatory diseases and cancer, " Pharmacological Reviews, vol. 61, no. 2, pp. 177-197, 2009.
124. D. M. Foureau, D. W. Mielcarz, L. C. Menard et al., "TLR9-dependent induction of intestinal defensins by Toxoplasma gondii, " The Journal of Immunology, vol. 184, no. 12, pp. 7022-7029, 2010.
125. A. M. Krieg, "CpG DNA: Trigger of sepsis, mediator of protection, or both" Scandinavian Journal of Infectious Diseases, vol. 35, no. 9, pp. 653-659, 2003.
126. D. M. Klinman, "Use of CpG oligodeoxynucleotides as immunoprotective agents, " Expert Opinion on Biological Therapy, vol. 4, no. 6, pp. 937-946, 2004.
127. J. Vollmer, R. Weeratna, P. Payette et al., "Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities, " European Journal of Immunology, vol. 34, no. 1, pp. 251-262, 2004.
128. G. Hartmann, J. Battiany, H. Poeck et al., "Rational design of new CpG oligonucleotides that combine B cell activation with high IFN induction in plasmacytoid dendritic cells, " European Journal of Immunology, vol. 33, no. 6, pp. 1633-1641, 2003.
129. J. D. Marshall, E. M. Hessel, J. Gregorio et al., "Novel chimeric immunomodulatory compounds containing short CpG oligodeoxyribonucleotides have differential activities in human cells, " Nucleic Acids Research, vol. 31, no. 17, pp. 5122-5133, 2003.
130. S. A. Halperin, S. Dobson, S. McNeil et al., "Comparison of the safety and immunogenicity of hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide and a licensed hepatitis B vaccine in healthy young adults, " Vaccine, vol. 24, no. 1, pp. 20-26, 2006.
131. M. Barry and C. Cooper, "Review of hepatitis B surface antigen-1018 ISS adjuvant-containing vaccine safety and efficacy, " Expert Opinion on BiologicalTherapy, vol. 7, no. 11, pp. 1731-1737, 2007.
132. C. Schmidt, "Clinical setbacks for toll-like receptor 9 agonists in cancer, " Nature Biotechnology, vol. 25, no. 8, pp. 825-826, 2007.
133. F. Ellouz, A. Adam, R. Ciorbaru, and E. Lederer, "Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives, " Biochemical and Biophysical Research Communications, vol. 59, no. 4, pp. 1317-1325, 1974.
134. S. E. Girardin, I. G. Boneca, J. Viala et al., "Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection, " The Journal of Biological Chemistry, vol. 278, no. 11, pp. 8869-8872, 2003.
135. K. Dzierzbicka, A. Wardowska, and P. Trzonkowski, "Recent developments in the synthesis and biological activity of muramylpeptides, " CurrentMedicinal Chemistry, vol. 18, no. 16, pp. 2438-2451, 2011.
136. P. T. P. Kaumaya, K. C. Foy, J. Garrett et al., "Phase I active immunotherapy with combination of two chimeric, human epidermal growth factor receptor 2, B-cell epitopes fused to a promiscuous T-cell epitope in patients with metastatic and/or recurrent solid tumors, " Journal of Clinical Oncology, vol. 27, no. 31, pp. 5270-5277, 2009.
137. S. Lee and M. T. Nguyen, "Recent advances of vaccine adjuvants for infectious diseases, " Immune Network, vol. 15, no. 2, pp. 51-57, 2015.
138. T. Querec, S. Bennouna, S. Alkan et al., "Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity, " Journal of Experimental Medicine, vol. 203, no. 2, pp. 413-424, 2006.
139. T. K. Ghosh, D. J. Mickelson, J. Fink et al., "Toll-like receptor (TLR) 2-9 agonists-induced cytokines and chemokines: I. Comparison with T cell receptor-induced responses, " Cellular Immunology, vol. 243, no. 1, pp. 48-57, 2006.
140. R. P. J. Lai, M. S. Seaman, P. Tonks et al., "Mixed adjuvant formulations reveal a new combination that elicit antibody response comparable to Freund's adjuvants, " PLoS ONE, vol. 7, no. 4, Article ID e35083, 2012.
141. S. P. Kasturi, I. Skountzou, R. A. Albrecht et al., "Programming the magnitude and persistence of antibody responses with innate immunity, " Nature, vol. 470, no. 7335, pp. 543-550, 2011.
142. G. Napolitani, A. Rinaldi, F. Bertoni, F. Sallusto, and A. Lanzavecchia, "Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells, " Nature Immunology, vol. 6, no. 8, pp. 769-776, 2005.
143. S. L. Hoffman, J. Vekemans, T. L. Richie, and P. E. Duffy, "The March towardmalaria vaccines, "AmericanJournal of Preventive Medicine, vol. 49, no. 6, supplement 4, pp. S319-S333, 2015.
144. N. Garçon, P. Chomez, and M. Van Mechelen, "GlaxoSmithKline adjuvant systems in vaccines: concepts, achievements and perspectives, " Expert Review of Vaccines, vol. 6, no. 5, pp. 723-739, 2007.
145. K. E. Kester, J. F. Cummings, O. Ofori-Anyinamet 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, " Journal of Infectious Diseases, vol. 200, no. 3, pp. 337-346, 2009.
146. G. Leroux-Roels, I. Leroux-Roels, F. Clement et al., "Evaluation of the immune response to RTS, S/AS01 and RTS, S/AS02 adjuvanted vaccines: randomized, double-blind study in malariana ve adults, " Human Vaccines and Immunotherapeutics, vol. 10, no. 8, pp. 2211-2219, 2014.
147. D. M. Harper, E. L. Franco, C. Wheeler et al., "Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: A randomised controlled trial, " The Lancet, vol. 364, no. 9447, pp. 1757-1765, 2004.
148. J. Paavonen, D. Jenkins, F. X. Bosch et al., "Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: An interim analysis of a phase III double-blind, randomised controlled trial, " The Lancet, vol. 369, no. 9580, pp. 2161-2170, 2007.
149. S. Thoelen, N. De Clercq, and N. Tornieporth, "A prophylactic hepatitis B vaccine with a novel adjuvant system, " Vaccine, vol. 19, no. 17-19, pp. 2400-2403, 2001.
150. M. M. Levine, "Immunization against bacterial diseases of the intestine, " Journal of Pediatric Gastroenterology and Nutrition, vol. 31, no. 4, pp. 336-355, 2000.
151. A. Z. Kapikian, Y. Hoshino, R. M. Chanock, and I. Perez-Schael, "Efficacy of a quadrivalent rhesus rotavirus-based human rotavirus vaccine aimed at preventing severe rotavirus diarrhea in infants and young children, " Journal of Infectious Diseases, vol. 174, supplement 1, pp. S65-S72, 1996.
152. R. B. Belshe, P. M. Mendelman, J. Treanor et al., "The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children, "TheNew England Journal ofMedicine, vol. 338, no. 20, pp. 1405-1412, 1998.
153. H. Savelkoul, V. Ferro, M. Strioga, and V. Schijns, "Choice and design of adjuvants for parenteral and mucosal vaccines, " Vaccines, vol. 3, no. 1, pp. 148-171, 2015.
154. B. L. Dickinson and J. D. Clements, "Dissociation of Escherichia coli heat-labile enterotoxin adjuvanticity from ADP-ribosyltransferase activity, " Infection and Immunity, vol. 63, no. 5, pp. 1617-1623, 1995.
155. G. Douce, C. Turcotte, I. Cropley et al., "Mutants of Escherichia coli heat-labile toxin lacking ADP-ribosyltransferase activity act as nontoxic, mucosal adjuvants, " Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 5, pp. 1644-1648, 1995.
156. J. D. Barackman, G. Ott, S. Pine, and D. T. O'Hagan, "Oral administration of influenza vaccine in combination with the adjuvants LT-K63 and LT-R72 induces potent immune responses comparable to or stronger than traditional intramuscular immunization, " Clinical and Diagnostic Laboratory Immunology, vol. 8, no. 3, pp. 652-657, 2001.
157. M. Marchetti, M. Rossi, V. Giannelli et al., "Protection against Helicobacter pylori infection in mice by intragastric vaccination with H. pylori antigens is achieved using a non-toxic mutant of E. coli heat-labile enterotoxin (LT) as adjuvant, " Vaccine, vol. 16, no. 1, pp. 33-37, 1998.
158. D. O'Hagan, C. Goldbeck, M. Ugozzoli, G. Ott, and R. L. Burke, "Intranasal immunization with recombinant gD2 reduces disease severity and mortality following genital challenge with herpes simplex virus type 2 in guinea pigs, " Vaccine, vol. 17, no. 18, pp. 2229-2236, 1999.
159. H. Jakobsen, D. Schulz, M. Pizza, R. Rappuoli, and I. Jónsdóttir, "Intranasal immunization with pneumococcal polysaccharide conjugate vaccines with nontoxic mutants of Escherichia coli heat-labile enterotoxins as adjuvants protects mice against invasive pneumococcal infections, " Infection and Immunity, vol. 67, no. 11, pp. 5892-5897, 1999.
160. E. J. Ryan, E. Mcneela, G. A. Murphy et al., "Mutants of Escherichia coli heat-labile toxin act as effective mucosal adjuvants for nasal delivery of an acellular pertussis vaccine: differential effects of the nontoxic AB complex and enzyme activity on Th1 and Th2 cells, " Infection and Immunity, vol. 67, no. 12, pp. 6270-6280, 1999.
161. J. H. Rhee, S. E. Lee, and S. Y. Kim, "Mucosal vaccine adjuvants update, " Clinical and Experimental Vaccine Research, vol. 1, no. 1, pp. 50-63, 2012.
162. M. C. Gagliardi, F. Sallusto, M. Marinaro et al., "Cholera toxin induces maturation of human dendritic cells and licences them forTh2 priming, " European Journal of Immunology, vol. 30, no. 8, pp. 2394-2403, 2000.
163. D. Y. Bargieri, D. S. Rosa, M. A. S. Lasaro, L. C. S. Ferreira, I. S. Soares, and M. M. Rodrigues, "Adjuvant requirement for successful immunization with recombinant derivatives of Plasmodium vivaxmerozoite surface protein-1 delivered via the intranasal route, "Memorias do Instituto Oswaldo Cruz, vol. 102, no. 3, pp. 313-317, 2007.
164. D. Ruane, A. Chorny, H. Lee et al., "Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinalimmune responses, "The Journal of Experimental Medicine, vol. 213, no. 1, pp. 53-73, 2016.
165. S. A. Moschos, V. W. Bramwell, S. Somavarapu, and H. O. Alpar, "Adjuvant synergy: The effects of nasal coadministration of adjuvants, " Immunology and Cell Biology, vol. 82, no. 6, pp. 628-637, 2004.
166. E. A. McNeela, I. Jabbal-Gill, L. Illum et al., "Intranasal immunization with genetically detoxified diphtheria toxin induces T cell responses in humans: enhancement of Th2 responses and toxin-neutralizing antibodies by formulation with chitosan, " Vaccine, vol. 22, no. 8, pp. 909-914, 2004.
167. K. H. G. Mills, C. Cosgrove, E. A. McNeela et al., "Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateralmucosal secretory immunoglobulin A, " Infection and Immunity, vol. 71, no. 2, pp. 726-732, 2003.
168. Y. Gong, L. Tao, F. Wang et al., "Chitosan as an adjuvant for a Helicobacter pylori therapeutic vaccine, " Molecular Medicine Reports, vol. 12, no. 3, pp. 4123-4132, 2015.
169. F. Verdier, "Non-clinical vaccine safety assessment, " Toxicology, vol. 174, no. 1, pp. 37-43, 2002.
170. M. J. Brennan, "The US food and drug administration provides a pathway for licensing vaccines for global diseases, " PLoS Medicine, vol. 6, no. 7, Article ID e1000095, 2009.
171. T. E. M. Agency, Guideline on Adjuvants in Vaccines, T. E. M. Agency, London, UK, 2005.