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Review article: Biomedical intelligence

Vol. 144 No. 2122 (2014)

Vaccine adjuvants – understanding molecular mechanisms to improve vaccines

  • Adrian Egli
  • Deanna Santer
  • Khaled Barakat
  • Martin Zand
  • Aviad Levin
  • Madeleine Vollmer
  • Maja Weisser
  • Nina Khanna
  • Deepali Kumar
  • Lorne Tyrrell
  • Michael Houghton
  • Manuel Battegay
  • Daire O'Shea
DOI
https://doi.org/10.4414/smw.2014.13940
Cite this as:
Swiss Med Wkly. 2014;144:w13940
Published
18.05.2014

Summary

Infectious pathogens are responsible for high utilisation of healthcare resources globally. Attributable morbidity and mortality remains exceptionally high. Vaccines offer the potential to prime a pathogen-specific immune response and subsequently reduce disease burden. Routine vaccination has fundamentally altered the natural history of many frequently observed and serious infections. Vaccination is also recommended for persons at increased risk of severe vaccine-preventable disease. Many current nonadjuvanted vaccines are poorly effective in the elderly and immunocompromised populations, resulting in nonprotective postvaccine antibody titres, which serve as surrogate markers for protection. The vaccine-induced immune response is influenced by: (i.) vaccine factors i.e., type and composition of the antigen(s), (ii.) host factors i.e., genetic differences in immune-signalling or senescence, and (iii.) external factors such as immunosuppressive drugs or diseases. Adjuvanted vaccines offer the potential to compensate for a lack of stimulation and improve pathogen-specific protection. In this review we use influenza vaccine as a model in a discussion of the different mechanisms of action of the available adjuvants. In addition, we will appraise new approaches using “vaccine-omics” to discover novel types of adjuvants.

References

  1. Riedel S. Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent). 2005;18(1):21–5. PubMed PMID: 16200144. Pubmed Central PMCID: 1200696. Epub 2005/10/04.
  2. von Behring E, Kitasato S. [The mechanism of diphtheria immunity and tetanus immunity in animals. 1890]. Mol Immunol. 1991;28(12):1317, 9–20. PubMed PMID: 1749380. Epub 1991/12/01. Ueber das Zustandekommen der Diphtherie-Immunitat und der Tetanus-Immunitat bei Thieren. German.
  3. Marrack P, McKee AS, Munks MW. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol. 2009;9(4):287–93. PubMed PMID: 19247370. Pubmed Central PMCID: 3147301. Epub 2009/02/28.
  4. Medina RA, Garcia-Sastre A. Influenza A viruses: new research developments. Nat Rev Microbiol. 2011;9(8):590–603. PubMed PMID: 21747392. Epub 2011/07/13.
  5. Vilchez RA, McCurry K, Dauber J, Lacono A, Griffith B, Fung J, et al. Influenza virus infection in adult solid organ transplant recipients. Am J Transplant. 2002;2(3):287–91. PubMed PMID: 12096793. Epub 2002/07/05.
  6. Weinstock DM, Gubareva LV, Zuccotti G. Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient. N Engl J Med. 2003;348(9):867–8. PubMed PMID: 12606750. Epub 2003/02/28.
  7. Mertz D, Kim TH, Johnstone J, Lam PP, Science M, Kuster SP, et al. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis. BMJ. 2013;347:f5061. PubMed PMID: 23974637.
  8. Dormitzer PR, Galli G, Castellino F, Golding H, Khurana S, Del Giudice G, et al. Influenza vaccine immunology. Immunol Rev. 2011;239(1):167–77. PubMed PMID: 21198671. Epub 2011/01/05.
  9. Garcia-Sastre A. Induction and evasion of type I interferon responses by influenza viruses. Virus Res. 2011;162(1–2):12–8. PubMed PMID: 22027189. Epub 2011/10/27.
  10. Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med. 2009;206(1):79–87. PubMed PMID: 19139171. Pubmed Central PMCID: 2626661. Epub 2009/01/14.
  11. Kreijtz JH, Fouchier RA, Rimmelzwaan GF. Immune responses to influenza virus infection. Virus Res. 2011;162(1–2):19–30. PubMed PMID: 21963677. Epub 2011/10/04.
  12. Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, et al. Systems biology of vaccination for seasonal influenza in humans. Nat Immunol. 2011;12(8):786–95. PubMed PMID: 21743478. Pubmed Central PMCID: 3140559. Epub 2011/07/12.
  13. Chiu C, Wrammert J, Li GM, McCausland M, Wilson PC, Ahmed R. Cross-reactive humoral responses to influenza and their implications for a universal vaccine. Annals of the New York Academy of Sciences. 2013;1283:13–21. PubMed PMID: 23405860.
  14. Corti D, Lanzavecchia A. Broadly neutralizing antiviral antibodies. Annu Rev Immunol. 2013;31:705–42. PubMed PMID: 23330954.
  15. Bachmann MF, Zinkernagel RM. Neutralizing antiviral B cell responses. Annu Rev Immunol. 1997;15:235–70. PubMed PMID: 9143688. Epub 1997/01/01.
  16. Neefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 2011;11(12):823–36. PubMed PMID: 22076556. Epub 2011/11/15.
  17. Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010 Jan 15;327(5963):291–5. PubMed PMID: 20075244. Pubmed Central PMCID: 3645875. Epub 2010/01/16.
  18. Aoshi T, Koyama S, Kobiyama K, Akira S, Ishii KJ. Innate and adaptive immune responses to viral infection and vaccination. Curr Opin Virol. 2011;1(4):226–32. PubMed PMID: 22440781. Epub 2012/03/24.
  19. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7–mediated recognition of single-stranded RNA. Science. 2004 5;303(5663):1529–31. PubMed PMID: 14976261. Epub 2004/02/21.
  20. Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science. 2006;314(5801):997–1001. PubMed PMID: 17038589. Epub 2006/10/14.
  21. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227–42. PubMed PMID: 23470321. Epub 2013/03/09.
  22. Sealy R, Surman S, Hurwitz JL, Coleclough C. Antibody response to influenza infection of mice: different patterns for glycoprotein and nucleocapsid antigens. Immunology. 2003;108(4):431–9. PubMed PMID: 12667204. Pubmed Central PMCID: 1782924. Epub 2003/04/02.
  23. Lee BO, Rangel-Moreno J, Moyron-Quiroz JE, Hartson L, Makris M, Sprague F, et al. CD4 T cell-independent antibody response promotes resolution of primary influenza infection and helps to prevent reinfection. J Immunol. 2005;175(9):5827–38. PubMed PMID: 16237075. Epub 2005/10/21.
  24. Toporovski R, Morrow MP, Weiner DB. Interferons as potential adjuvants in prophylactic vaccines. Expert Opin Biol Ther. 2010;10(10):1489–500. PubMed PMID: 20836750. Epub 2010/09/15.
  25. Halloran PF, Urmson J, Van der Meide PH, Autenried P. Regulation of MHC expression in vivo. II. IFN-alpha/beta inducers and recombinant IFN-alpha modulate MHC antigen expression in mouse tissues. J Immunol. 1989;142(12):4241–7. PubMed PMID: 2498428. Epub 1989/06/15.
  26. Swain SL, McKinstry KK, Strutt TM. Expanding roles for CD4+ T cells in immunity to viruses. Nature Reviews Immunology. 2012:doi:10.1038/nri3152.
  27. Billiau A, Matthys P. Interferon-gamma: a historical perspective. Cytokine Growth Factor Rev. 2009;20(2):97–113. PubMed PMID: 19268625.
  28. Clegg CH, Roque R, Van Hoeven N, Perrone L, Baldwin SL, Rininger JA, et al. Adjuvant solution for pandemic influenza vaccine production. Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17585–90. PubMed PMID: 23045649. Pubmed Central PMCID: 3491477.
  29. Bright RA, Carter DM, Daniluk S, Toapanta FR, Ahmad A, Gavrilov V, et al. Influenza virus-like particles elicit broader immune responses than whole virion inactivated influenza virus or recombinant hemagglutinin. Vaccine. 2007;25(19):3871–8. PubMed PMID: 17337102.
  30. Goldberg AL, Cascio P, Saric T, Rock KL. The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides. Mol Immunol. 2002;39(3–4):147–64. PubMed PMID: 12200047.
  31. Mari N, Hercor M, Denanglaire S, Leo O, Andris F. The capacity of Th2 lymphocytes to deliver B-cell help requires expression of the transcription factor STAT3. Eur J Immunol. 2013. PubMed PMID: 23504518. Epub 2013/03/19.
  32. Kamburova EG, Koenen HJ, Boon L, Hilbrands LB, Joosten I. In vitro effects of rituximab on the proliferation, activation and differentiation of human B cells. Am J Transplant. 2012;12(2):341–50. PubMed PMID: 22070501. Epub 2011/11/11.
  33. Moschovakis GL, Bubke A, Dittrich-Breiholz O, Braun A, Prinz I, Kremmer E, et al. Deficient CCR7 signaling promotes TH2 polarization and B-cell activation in vivo. Eur J Immunol. 2012;42(1):48–57. PubMed PMID: 21969271. Epub 2011/10/05.
  34. Honda K, Taniguchi T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol. 2006 Sep;6(9):644–58. PubMed PMID: 16932750. Epub 2006/08/26.
  35. Lohoff M, Mak TW. Roles of interferon-regulatory factors in T-helper-cell differentiation. Nat Rev Immunol. 2005;5(2):125–35. PubMed PMID: 15688040. Epub 2005/02/03.
  36. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007;7(6):454–65. PubMed PMID: 17525754. Epub 2007/05/26.
  37. McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol. 2012;12(1):24–34. PubMed PMID: 22158414. Epub 2011/12/14.
  38. King C. New insights into the differentiation and function of T follicular helper cells. Nat Rev Immunol. 2009;9(11):757–66. PubMed PMID: 19855402. Epub 2009/10/27.
  39. Pallikkuth S, Parmigiani A, Silva SY, George VK, Fischl M, Pahwa R, et al. Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine. Blood. 2012 Aug 2;120(5):985–93. PubMed PMID: 22692510. Pubmed Central PMCID: 3412336. Epub 2012/06/14.
  40. Pallikkuth S, Pilakka Kanthikeel S, Silva SY, Fischl M, Pahwa R, Pahwa S. Upregulation of IL-21 receptor on B cells and IL-21 secretion distinguishes novel 2009 H1N1 vaccine responders from nonresponders among HIV-infected persons on combination antiretroviral therapy. J Immunol. 2011;186(11):6173–81. PubMed PMID: 21531891. Pubmed Central PMCID: 3170914.
  41. Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol. 2002;2(7):465–75. PubMed PMID: 12094221. Epub 2002/07/03.
  42. Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, et al. Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol. 2009;30(7):325–33. PubMed PMID: 19541535. Epub 2009/06/23.
  43. Rappuoli R, Dormitzer PR. Influenza: options to improve pandemic preparation. Science. 2012 Jun 22;336(6088):1531–3. PubMed PMID: 22723412. Epub 2012/06/23.
  44. Rappuoli R, Mandl CW, Black S, De Gregorio E. Vaccines for the twenty-first century society. Nat Rev Immunol. 2011;11(12):865–72. PubMed PMID: 22051890. Epub 2011/11/05.
  45. Sambhara S, McElhaney JE. Immunosenescence and influenza vaccine efficacy. Curr Top Microbiol Immunol. 2009;333:413–29. PubMed PMID: 19768417. Epub 2009/09/22.
  46. Liu WM, van der Zeijst BA, Boog CJ, Soethout EC. Aging and impaired immunity to influenza viruses: implications for vaccine development. Hum Vaccin. 2011;7 Suppl:94–8. PubMed PMID: 21301210. Epub 2011/02/09.
  47. Beck CR, McKenzie BC, Hashim AB, Harris RC, Nguyen-Van-Tam JS. Influenza vaccination for immunocompromised patients: systematic review and meta-analysis by etiology. J Infect Dis. 2012;206(8):1250–9. PubMed PMID: 22904335. Epub 2012/08/21.
  48. Nicoll A, Sprenger M. Low effectiveness undermines promotion of seasonal influenza vaccine. Lancet Infect Dis. 2013;13(1):7–9. PubMed PMID: 23257219. Epub 2012/12/22.
  49. Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24(8):1159–69. PubMed PMID: 16213065. Epub 2005/10/11.
  50. Jefferson T, Rivetti D, Rivetti A, Rudin M, Di Pietrantonj C, Demicheli V. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet. 2005;366(9492):1165–74. PubMed PMID: 16198765. Epub 2005/10/04.
  51. Nichol KL, Nordin JD, Nelson DB, Mullooly JP, Hak E. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med. 2007;357(14):1373–81. PubMed PMID: 17914038. Epub 2007/10/05.
  52. Baluch A, Humar A, Eurich D, Egli A, Liacini A, Hoschler K, et al. Randomized controlled trial of high-dose intradermal versus standard-dose intramuscular influenza vaccine in organ transplant recipients. Am J Transplant. 2013;13(4):1026–33. PubMed PMID: 23406320. Epub 2013/02/15.
  53. Kumar A, Zarychanski R, Pinto R, Cook DJ, Marshall J, Lacroix J, et al. Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA. 2009;302(17):1872–9. PubMed PMID: 19822627. Epub 2009/10/14.
  54. Parish CR, Liew FY. Immune response to chemically modified flagellin. 3. Enhanced cell-mediated immunity during high and low zone antibody tolerance to flagellin. J Exp Med. 1972;135(2):298–311. PubMed PMID: 5060292. Pubmed Central PMCID: 2180527. Epub 1972/02/01.
  55. Randolph DA, Huang G, Carruthers CJ, Bromley LE, Chaplin DD. The role of CCR7 in TH1 and TH2 cell localization and delivery of B cell help in vivo. Science. 1999;286(5447):2159–62. PubMed PMID: 10591648. Epub 1999/12/11.
  56. Serre K, Mohr E, Benezech C, Bird R, Khan M, Caamano JH, et al. Selective effects of NF-kappaB1 deficiency in CD4(+) T cells on Th2 and TFh induction by alum-precipitated protein vaccines. Eur J Immunol. 2011;41(6):1573–82. PubMed PMID: 21469117. Epub 2011/04/07.
  57. Harris N, Gause WC. To B or not to B: B cells and the Th2–type immune response to helminths. Trends Immunol. 2011;32(2):80–8. PubMed PMID: 21159556. Pubmed Central PMCID: 3076625. Epub 2010/12/17.
  58. Nauta JJ, Beyer WE, Osterhaus AD. On the relationship between mean antibody level, seroprotection and clinical protection from influenza. Biologicals. 2009;37(4):216–21. PubMed PMID: 19268607. Epub 2009/03/10.
  59. Coudeville L, Bailleux F, Riche B, Megas F, Andre P, Ecochard R. Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model. BMC Med Res Methodol. 2010;10:18. PubMed PMID: 20210985. Pubmed Central PMCID: 2851702. Epub 2010/03/10.
  60. Coler RN, Bertholet S, Moutaftsi M, Guderian JA, Windish HP, Baldwin SL, et al. Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant. PLoS One. 2011;6(1):e16333. PubMed PMID: 21298114. Pubmed Central PMCID: 3027669. Epub 2011/02/08.
  61. Baudner BC, Ronconi V, Casini D, Tortoli M, Kazzaz J, Singh M, et al. MF59 emulsion is an effective delivery system for a synthetic TLR4 agonist (E6020). Pharm Res. 2009;26(6):1477–85. PubMed PMID: 19255727. Epub 2009/03/04.
  62. Glenny AT, Pope CG, Waddington H, Wallace U. Immunological notes. XVII–XXIV. J Pathol Bacteriol. 1926;29:31–40.
  63. Ng G, Sharma K, Ward SM, Desrosiers MD, Stephens LA, Schoel WM, et al. Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells. Immunity. 2008;29(5):807–18. PubMed PMID: 18993083. Pubmed Central PMCID: 2642965. Epub 2008/11/11.
  64. Kool M, Soullie T, van Nimwegen M, Willart MA, Muskens F, Jung S, et al. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med. 2008;205(4):869–82. PubMed PMID: 18362170. Pubmed Central PMCID: 2292225. Epub 2008/03/26.
  65. Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453(7198):1122–6. PubMed PMID: 18496530. Epub 2008/05/23.
  66. Li H, Nookala S, Re F. Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1beta and IL-18 release. J Immunol. 2007;178(8):5271–6. PubMed PMID: 17404311. Epub 2007/04/04.
  67. Li H, Willingham SB, Ting JP, Re F. Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol. 2008;181(1):17–21. PubMed PMID: 18566365. Pubmed Central PMCID: 2587213. Epub 2008/06/21.
  68. Mannhalter JW, Neychev HO, Zlabinger GJ, Ahmad R, Eibl MM. 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. 1985;61(1):143–51. PubMed PMID: 3876178. Pubmed Central PMCID: 1577243. Epub 1985/07/01.
  69. Ulanova M, Tarkowski A, Hahn-Zoric M, Hanson LA. The Common vaccine adjuvant aluminum hydroxide up-regulates accessory properties of human monocytes via an interleukin-4-dependent mechanism. Infect Immun. 2001;69(2):1151–9. PubMed PMID: 11160013. Pubmed Central PMCID: 97997. Epub 2001/02/13.
  70. Sokolovska A, Hem SL, HogenEsch H. Activation of dendritic cells and induction of CD4(+) T cell differentiation by aluminum-containing adjuvants. Vaccine. 2007;25(23):4575–85. PubMed PMID: 17485153. Epub 2007/05/09.
  71. Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R. Toll-like receptors control activation of adaptive immune responses. Nat Immunol. 2001;2(10):947–50. PubMed PMID: 11547333. Epub 2001/09/08.
  72. Kopf M, Le Gros G, Bachmann M, Lamers MC, Bluethmann H, Kohler G. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature. 1993;362(6417):245–8. PubMed PMID: 8384701. Epub 1993/03/18.
  73. Brewer JM, Conacher M, Satoskar A, Bluethmann H, Alexander J. 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. 1996;26(9):2062–6. PubMed PMID: 8814247. Epub 1996/09/01.
  74. Manzoli L, De Vito C, Salanti G, D'Addario M, Villari P, Ioannidis JP. Meta-analysis of the immunogenicity and tolerability of pandemic influenza A 2009 (H1N1) vaccines. PLoS One. 2011;6(9):e24384. PubMed PMID: 21915319. Pubmed Central PMCID: 3167852. Epub 2011/09/15.
  75. Bachmann MF, Jennings GT. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol. 2010;10(11):787–96. PubMed PMID: 20948547. Epub 2010/10/16.
  76. Dupuis M, Murphy TJ, Higgins D, Ugozzoli M, van Nest G, Ott G, et al. Dendritic cells internalize vaccine adjuvant after intramuscular injection. Cell Immunol. 1998;186(1):18–27. PubMed PMID: 9637761. Epub 1998/06/25.
  77. Seubert A, Calabro S, Santini L, Galli B, Genovese A, Valentini S, 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 U S A. 2011;108(27):11169–74. PubMed PMID: 21690334. Pubmed Central PMCID: 3131326. Epub 2011/06/22.
  78. He B, Santamaria R, Xu W, Cols M, Chen K, Puga I, et al. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nat Immunol. 2010;11(9):836–45. PubMed PMID: 20676093. Pubmed Central PMCID: 3047500. Epub 2010/08/03.
  79. Ott G, Barchfeld GL, Chernoff D, Radhakrishnan R, van Hoogevest P, Van Nest G. MF59. Design and evaluation of a safe and potent adjuvant for human vaccines. Pharm Biotechnol. 1995;6:277–96. PubMed PMID: 7551221. Epub 1995/01/01.
  80. Dupuis M, Denis-Mize K, LaBarbara A, Peters W, Charo IF, McDonald DM, et al. Immunization with the adjuvant MF59 induces macrophage trafficking and apoptosis. Eur J Immunol. 2001;31(10):2910–8. PubMed PMID: 11592066. Epub 2001/10/10.
  81. Hui G, Hashimoto C. The requirement of CD80, CD86, and ICAM-1 on the ability of adjuvant formulations to potentiate antibody responses to a Plasmodium falciparum blood-stage vaccine. Vaccine. 2007;25(51):8549–56. PubMed PMID: 18006124. Pubmed Central PMCID: 2211737. Epub 2007/11/17.
  82. O'Hagan DT, Ott GS, De Gregorio E, Seubert A. The mechanism of action of MF59 – an innately attractive adjuvant formulation. Vaccine. 2012;30(29):4341–8. PubMed PMID: 22682289. Epub 2012/06/12.
  83. Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C, et al. Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci U S A. 2008;105(30):10501–6. PubMed PMID: 18650390. Pubmed Central PMCID: 2483233. Epub 2008/07/25.
  84. Morel S, Didierlaurent A, Bourguignon P, Delhaye S, Baras B, Jacob V, et al. Adjuvant System AS03 containing alpha-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine. 2011;29(13):2461–73. PubMed PMID: 21256188. Epub 2011/01/25.
  85. Dupuis M, McDonald DM, Ott G. Distribution of adjuvant MF59 and antigen gD2 after intramuscular injection in mice. Vaccine. 1999;18(5–6):434–9. PubMed PMID: 10519932. Epub 1999/10/16.
  86. Baldo V, Baldovin T, Floreani A, Carraro AM, Trivello R. MF59–adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18–60 years of age) with chronic diseases who are at risk of post-influenza complications. Vaccine. 2007;25(20):3955–61. PubMed PMID: 17383057. Epub 2007/03/27.
  87. Podda A. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59–adjuvanted vaccine. Vaccine. 2001;19(17–19):2673–80. PubMed PMID: 11257408. Epub 2001/03/21.
  88. Gasparini R, Pozzi T, Montomoli E, Fragapane E, Senatore F, Minutello M, et al. Increased immunogenicity of the MF59–adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects. Eur J Epidemiol. 2001;17(2):135–40. PubMed PMID: 11599686. Epub 2001/10/16.
  89. Squarcione S, Sgricia S, Biasio LR, Perinetti E. Comparison of the reactogenicity and immunogenicity of a split and a subunit-adjuvanted influenza vaccine in elderly subjects. Vaccine. 2003;21(11–12):1268–74. PubMed PMID: 12559808. Epub 2003/02/01.
  90. Banzhoff A, Nacci P, Podda A. A new MF59–adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis. Gerontology. 2003;49(3):177–84. PubMed PMID: 12679609. Epub 2003/04/08.
  91. Vesikari T, Pellegrini M, Karvonen A, Groth N, Borkowski A, O'Hagan DT, et al. Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant. Pediatr Infect Dis J. 2009;28(7):563–71. PubMed PMID: 19561422. Epub 2009/06/30.
  92. Khurana S, Verma N, Yewdell JW, Hilbert AK, Castellino F, Lattanzi M, et al. MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines. Sci Transl Med. 2011;3(85):85ra48. PubMed PMID: 21632986. Pubmed Central PMCID: 3501657. Epub 2011/06/03.
  93. Beran J, Abdel-Messih IA, Raupachova J, Hobzova L, Fragapane E. A phase III, randomized, open-label study to assess the tolerability and immunogenicity of an H5N1 influenza vaccine administered to healthy adults with a 1-, 2-, 3-, or 6-week interval between first and second doses. Clin Ther. 2010;32(13):2186–97. PubMed PMID: 21316535. Epub 2011/02/15.
  94. Vesikari T, Karvonen A, Tilman S, Borkowski A, Montomoli E, Banzhoff A, et al. Immunogenicity and safety of MF59–adjuvanted H5N1 influenza vaccine from infancy to adolescence. Pediatrics. 2010;126(4):e762–70. PubMed PMID: 20819892. Epub 2010/09/08.
  95. Stephenson I, Gust I, Kieny MP, Pervikov Y. Development and evaluation of influenza pandemic vaccines. Lancet Infect Dis. 2006;6(2):71–2. PubMed PMID: 16439326. Epub 2006/01/28.
  96. Nicholson KG, Colegate AE, Podda A, Stephenson I, Wood J, Ypma E, et al. Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet. 2001;357(9272):1937–43. PubMed PMID: 11425416. Epub 2001/06/27.
  97. Del Giudice G, Hilbert AK, Bugarini R, Minutello A, Popova O, Toneatto D, et al. An MF59–adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine. Vaccine. 2006;24(16):3063–5. PubMed PMID: 16464520. Epub 2006/02/09.
  98. Stephenson I, Bugarini R, Nicholson KG, Podda A, Wood JM, Zambon MC, et al. Cross-reactivity 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. J Infect Dis. 2005;191(8):1210–5. PubMed PMID: 15776364. Epub 2005/03/19.
  99. Langley JM, Frenette L, Ferguson L, Riff D, Sheldon E, Risi G, et al. Safety and cross-reactive immunogenicity of candidate AS03–adjuvanted prepandemic H5N1 influenza vaccines: a randomized controlled phase 1/2 trial in adults. J Infect Dis. 2010;201(11):1644–53. PubMed PMID: 20423222. Epub 2010/04/29.
  100. Ansaldi F, Zancolli M, Durando P, Montomoli E, Sticchi L, Del Giudice G, et al. Antibody response against heterogeneous circulating influenza virus strains elicited by MF59- and non-adjuvanted vaccines during seasons with good or partial matching between vaccine strain and clinical isolates. Vaccine. 2010;28(25):4123–9. PubMed PMID: 20433807. Epub 2010/05/04.
  101. Arguedas A, Soley C, Abdelnour A, Sales V, Lindert K, Della Cioppa G, et al. Assessment of the safety, tolerability and kinetics of the immune response to A/H1N1v vaccine formulations with and without adjuvant in healthy pediatric subjects from 3 through 17 years of age. Hum Vaccin. 2011;7(1):58–66. PubMed PMID: 21285531. Epub 2011/02/03.
  102. Elkayam O, Amir S, Mendelson E, Schwaber M, Grotto I, Wollman J, et al. Efficacy and safety of vaccination against pandemic 2009 influenza A (H1N1) virus among patients with rheumatic diseases. Arthritis Care Res (Hoboken). 2011;63(7):1062–7. PubMed PMID: 21425247. Epub 2011/03/23.
  103. Clark TW, Pareek M, Hoschler K, Dillon H, Nicholson KG, Groth N, et al. Trial of 2009 influenza A (H1N1) monovalent MF59–adjuvanted vaccine. N Engl J Med. 2009;361(25):2424–35. PubMed PMID: 19745215. Epub 2009/09/12.
  104. Mbow ML, De Gregorio E, Valiante NM, Rappuoli R. New adjuvants for human vaccines. Curr Opin Immunol. 2010;22(3):411–6. PubMed PMID: 20466528. Epub 2010/05/15.
  105. Martin JT. Development of an adjuvant to enhance the immune response to influenza vaccine in the elderly. Biologicals. 1997;25(2):209–13. PubMed PMID: 9236054. Epub 1997/06/01.
  106. Iob A, Brianti G, Zamparo E, Gallo T. Evidence of increased clinical protection of an MF59–adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy. Epidemiol Infect. 2005;133(4):687–93. PubMed PMID: 16050515. Pubmed Central PMCID: 2870297. Epub 2005/07/30.
  107. Chu DW, Hwang SJ, Lim FS, Oh HM, Thongcharoen P, Yang PC, et al. Immunogenicity and tolerability of an AS03(A)-adjuvanted prepandemic influenza vaccine: a phase III study in a large population of Asian adults. Vaccine. 2009;27(52):7428–35. PubMed PMID: 19683087. Epub 2009/08/18.
  108. Leroux-Roels G. Prepandemic H5N1 influenza vaccine adjuvanted with AS03: a review of the pre-clinical and clinical data. Expert Opin Biol Ther. 2009;9(8):1057–71. PubMed PMID: 19555313. Epub 2009/06/27.
  109. Schwarz TF, Horacek T, Knuf M, Damman HG, Roman F, Drame M, et al. Single dose vaccination with AS03–adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine. 2009;27(45):6284–90. PubMed PMID: 19856521. Epub 2009/10/27.
  110. Waddington CS, Walker WT, Oeser C, Reiner A, John T, Wilkins S, et al. Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study. Bmj. 2010;340:c2649. PubMed PMID: 20508026. Pubmed Central PMCID: 2877808. Epub 2010/05/29.
  111. Manuel O, Pascual M, Hoschler K, Giulieri S, Alves D, Ellefsen K, et al. Humoral response to the influenza A H1N1/09 monovalent AS03–adjuvanted vaccine in immunocompromised patients. Clin Infect Dis. 2011;52(2):248–56. PubMed PMID: 21288852. Epub 2011/02/04.
  112. Heijmans S, De Meulemeester M, Reynders P, Giet D, Demanet E, Devresse PY, et al. Immunogenicity profile of a 3.75–mug hemagglutinin pandemic rH5N1 split virion AS03A-adjuvanted vaccine in elderly persons: a randomized trial. J Infect Dis. 2011;203(8):1054–62. PubMed PMID: 21450995. Pubmed Central PMCID: 3068020. Epub 2011/04/01.
  113. Carmona A, Omenaca F, Tejedor JC, Merino JM, Vaman T, Dieussaert I, et al. Immunogenicity and safety of AS03–adjuvanted 2009 influenza A H1N1 vaccine in children 6–35 months. Vaccine. 2010;28(36):5837–44. PubMed PMID: 20600478. Epub 2010/07/06.
  114. Garcia-Sicilia J, Gillard P, Carmona A, Tejedor JC, Aristegui J, Merino JM, et al. Immunogenicity and safety of AS03–adjuvanted H1N1 pandemic vaccines in children and adolescents. Vaccine. 2011;29(26):4353–61. PubMed PMID: 21504774. Epub 2011/04/21.
  115. Skowronski DM, Janjua NZ, De Serres G, Hottes TS, Dickinson JA, Crowcroft N, et al. Effectiveness of AS03 adjuvanted pandemic H1N1 vaccine: case-control evaluation based on sentinel surveillance system in Canada, autumn 2009. Bmj. 2011;342:c7297. PubMed PMID: 21292718. Pubmed Central PMCID: 3033439. Epub 2011/02/05.
  116. Saenz R, Souza Cda S, Huang CT, Larsson M, Esener S, Messmer D. HMGB1–derived peptide acts as adjuvant inducing immune responses to peptide and protein antigen. Vaccine. 2010;28(47):7556–62. PubMed PMID: 20800114. Pubmed Central PMCID: 2963688. Epub 2010/08/31.
  117. Clawson C, Huang CT, Futalan D, Seible DM, Saenz R, Larsson M, et al. Delivery of a peptide via poly(D,L-lactic-co-glycolic) acid nanoparticles enhances its dendritic cell-stimulatory capacity. Nanomedicine. 2010;6(5):651–61. PubMed PMID: 20348031. Pubmed Central PMCID: 2947606. Epub 2010/03/30.
  118. Aucouturier J, Dupuis L, Deville S, Ascarateil S, Ganne V. Montanide ISA 720 and 51: a new generation of water in oil emulsions as adjuvants for human vaccines. Expert Rev Vaccines. 2002;1(1):111–8. PubMed PMID: 12908518. Epub 2003/08/12.
  119. Enoksson M, Ejendal KF, McAlpine S, Nilsson G, Lunderius-Andersson C. Human cord blood-derived mast cells are activated by the Nod1 agonist M-TriDAP to release pro-inflammatory cytokines and chemokines. J Innate Immun. 2011;3(2):142–9. PubMed PMID: 21099203. Epub 2010/11/26.
  120. Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science. 2007;316(5831):1628–32. PubMed PMID: 17569868. Epub 2007/06/16.
  121. Raman VS, Bhatia A, Picone A, Whittle J, Bailor HR, O'Donnell J, et al. Applying TLR synergy in immunotherapy: implications in cutaneous leishmaniasis. J Immunol. 2010;185(3):1701–10. PubMed PMID: 20601594. Pubmed Central PMCID: 3109724. Epub 2010/07/06.
  122. Buwitt-Beckmann U, Heine H, Wiesmuller KH, Jung G, Brock R, Akira S, et al. Toll-like receptor 6–independent signaling by diacylated lipopeptides. Eur J Immunol. 2005;35(1):282–9. PubMed PMID: 15580661. Epub 2004/12/08.
  123. Yan W, Chen WC, Liu Z, Huang L. Bryostatin-I: a dendritic cell stimulator for chemokines induction and a promising adjuvant for a peptide based cancer vaccine. Cytokine. 2010;52(3):238–44. PubMed PMID: 20869878. Epub 2010/09/28.
  124. Sasaki S, Fukushima J, Hamajima K, Ishii N, Tsuji T, Xin KQ, et al. Adjuvant effect of Ubenimex on a DNA vaccine for HIV-1. Clin Exp Immunol. 1998;111(1):30–5. PubMed PMID: 9472658. Pubmed Central PMCID: 1904860. Epub 1998/02/24.
  125. Rey-Ladino J, Ross AG, Cripps AW, McManus DP, Quinn R. Natural products and the search for novel vaccine adjuvants. Vaccine. 2011;29(38):6464–71. PubMed PMID: 21787827. Epub 2011/07/27.
  126. Flower DR. Systematic identification of small molecule adjuvants. Expert Opin Drug Discov. 2012;7(9):807–17. PubMed PMID: 22724523. Epub 2012/06/26.
  127. Suzuki H, Wang B, Shivji GM, Toto P, Amerio P, Tomai MA, et al. Imiquimod, a topical immune response modifier, induces migration of Langerhans cells. J Invest Dermatol. 2000;114(1):135–41. PubMed PMID: 10620129. Epub 2000/01/05.
  128. Tomai MA, Miller RL, Lipson KE, Kieper WC, Zarraga IE, Vasilakos JP. Resiquimod and other immune response modifiers as vaccine adjuvants. Expert Rev Vaccines. 2007;6(5):835–47. PubMed PMID: 17931162. Epub 2007/10/13.
  129. Ma F, Zhang J, Zhang C. The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice. Cell Mol Immunol. 2010;7(5):381–8. PubMed PMID: 20543857. Epub 2010/06/15.
  130. Klinman D, Shirota H, Tross D, Sato T, Klaschik S. Synthetic oligonucleotides as modulators of inflammation. J Leukoc Biol. 2008;84(4):958–64. PubMed PMID: 18430787. Pubmed Central PMCID: 2538593. Epub 2008/04/24.
  131. Luganini A, Caposio P, Landolfo S, Gribaudo G. Phosphorothioate-modified oligodeoxynucleotides inhibit human cytomegalovirus replication by blocking virus entry. Antimicrob Agents Chemother. 2008;52(3):1111–20. PubMed PMID: 18180342. Pubmed Central PMCID: 2258505. Epub 2008/01/09.
  132. Ballas ZK, Krieg AM, Warren T, Rasmussen W, Davis HL, Waldschmidt M, et al. Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs. J Immunol. 2001;167(9):4878–86. PubMed PMID: 11673492. Epub 2001/10/24.
  133. Stacey KJ, Blackwell JM. Immunostimulatory DNA as an adjuvant in vaccination against Leishmania major. Infect Immun. 1999;67(8):3719–26. PubMed PMID: 10417129. Pubmed Central PMCID: 96645. Epub 1999/07/23.
  134. Cui Z, Qiu F. Synthetic double-stranded RNA poly(I:C) as a potent peptide vaccine adjuvant: therapeutic activity against human cervical cancer in a rodent model. Cancer Immunol Immunother. 2006;55(10):1267–79. PubMed PMID: 16362407. Epub 2005/12/20.
  135. Buschow SI, Lasonder E, van Deutekom HW, Oud MM, Beltrame L, Huynen MA, et al. Dominant processes during human dendritic cell maturation revealed by integration of proteome and transcriptome at the pathway level. J Proteome Res. 2010;9(4):1727–37. PubMed PMID: 20131907. Epub 2010/02/06.
  136. Poland GA, Ovsyannikova IG, Kennedy RB, Haralambieva IH, Jacobson RM. Vaccinomics and a new paradigm for the development of preventive vaccines against viral infections. OMICS. 2011;15(9):625–36. PubMed PMID: 21732819. Pubmed Central PMCID: 3166201. Epub 2011/07/08.
  137. Haralambieva IH, Oberg AL, Dhiman N, Ovsyannikova IG, Kennedy RB, Grill DE, et al. High-dimensional gene expression profiling studies in high and low responders to primary smallpox vaccination. J Infect Dis. 2012;206(10):1512–20. PubMed PMID: 22949304. Pubmed Central PMCID: 3475634. Epub 2012/09/06.
  138. Haralambieva IH, Ovsyannikova IG, Pankratz VS, Kennedy RB, Jacobson RM, Poland GA. The genetic basis for interindividual immune response variation to measles vaccine: new understanding and new vaccine approaches. Expert Rev Vaccines. 2013;12(1):57–70. PubMed PMID: 23256739. Pubmed Central PMCID: 3570049. Epub 2012/12/22.
  139. Germain RN, Meier-Schellersheim M, Nita-Lazar A, Fraser ID. Systems biology in immunology: a computational modeling perspective. Annu Rev Immunol. 2011;29:527–85. PubMed PMID: 21219182. Pubmed Central PMCID: 3164774. Epub 2011/01/12.
  140. Umlauf BJ, Ovsyannikova IG, Haralambieva IH, Kennedy RB, Vierkant RA, Pankratz VS, et al. Correlations between vaccinia-specific immune responses within a cohort of armed forces members. Viral Immunol. 2011;24(5):415–20. PubMed PMID: 21958369. Pubmed Central PMCID: 3236101. Epub 2011/10/01.
  141. Kennedy RB, Ovsyannikova IG, Pankratz VS, Haralambieva IH, Vierkant RA, Jacobson RM, et al. Genome-wide genetic associations with IFNgamma response to smallpox vaccine. Hum Genet. 2012;131(9):1433–51. PubMed PMID: 22661280. Epub 2012/06/05.
  142. Ovsyannikova IG, Kennedy RB, O'Byrne M, Jacobson RM, Pankratz VS, Poland GA. Genome-wide association study of antibody response to smallpox vaccine. Vaccine. 2012;30(28):4182–9. PubMed PMID: 22542470. Pubmed Central PMCID: 3367131. Epub 2012/05/01.
  143. Davis NA, Crowe JE, Jr., Pajewski NM, McKinney BA. Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine. Genes Immun. 2010;11(8):630–6. PubMed PMID: 20613780. Pubmed Central PMCID: 3001955. Epub 2010/07/09.
  144. Haralambieva IH, Oberg AL, Ovsyannikova IG, Kennedy RB, Grill DE, Middha S, et al. Genome-wide characterization of transcriptional patterns in high and low antibody responders to rubella vaccination. PLoS One. 2013;8(5):e62149. PubMed PMID: 23658707. Pubmed Central PMCID: 3641062. Epub 2013/05/10.
  145. Fellay J, Frahm N, Shianna KV, Cirulli ET, Casimiro DR, Robertson MN, et al. Host genetic determinants of T cell responses to the MRKAd5 HIV-1 gag/pol/nef vaccine in the step trial. J Infect Dis. 2011;203(6):773–9. PubMed PMID: 21278214. Pubmed Central PMCID: 3071133. Epub 2011/02/01.
  146. Png E, Thalamuthu A, Ong RT, Snippe H, Boland GJ, Seielstad M. A genome-wide association study of hepatitis B vaccine response in an Indonesian population reveals multiple independent risk variants in the HLA region. Hum Mol Genet. 2011;20(19):3893–8. PubMed PMID: 21764829. Epub 2011/07/19.
  147. Miller EK, Dumitrescu L, Cupp C, Dorris S, Taylor S, Sparks R, et al. Atopy history and the genomics of wheezing after influenza vaccination in children 6–59 months of age. Vaccine. 2011;29(18):3431–7. PubMed PMID: 21396408. Pubmed Central PMCID: 3334304. Epub 2011/03/15.
  148. Querec TD, Akondy RS, Lee EK, Cao W, Nakaya HI, Teuwen D, et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol. 2009;10(1):116–25. PubMed PMID: 19029902. Epub 2008/11/26.
  149. Henn AD, Wu S, Qiu X, Ruda M, Stover M, Yang H, et al. High-resolution temporal response patterns to influenza vaccine reveal a distinct human plasma cell gene signature. Sci Rep. 2013;3:2327. PubMed PMID: 23900141.
  150. Bekeredjian-Ding I, Jego G. Toll-like receptors-sentries in the B-cell response. Immunology. 2009;128(3):311–23. PubMed PMID: 20067531. Pubmed Central PMCID: 2770679. Epub 2010/01/14.
  151. Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7(3):e33536. PubMed PMID: 22470453. Pubmed Central PMCID: 3314666. Epub 2012/04/04.
  152. Miller E, Andrews N, Stellitano L, Stowe J, Winstone AM, Shneerson J, et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. Bmj. 2013;346:f794. PubMed PMID: 23444425. Epub 2013/02/28.
  153. Hattotuwagama CK, Davies MN, Flower DR. Receptor-ligand binding sites and virtual screening. Curr Med Chem. 2006;13(11):1283–304. PubMed PMID: 16712470. Epub 2006/05/23.
  154. McInnes C. Virtual screening strategies in drug discovery. Curr Opin Chem Biol. 2007;11(5):494–502. PubMed PMID: 17936059. Epub 2007/10/16.
  155. Ripphausen P, Nisius B, Peltason L, Bajorath J. Quo vadis, virtual screening? A comprehensive survey of prospective applications. J Med Chem. 2010;53(24):8461–7. PubMed PMID: 20929257. Epub 2010/10/12.
  156. Bajorath J. Computational studies, virtual screening, and theoretical molecular models. J Med Chem. 2010;53(1):1–2. PubMed PMID: 20000613. Epub 2009/12/17.
  157. Charoenvit Y, Goel N, Whelan M, Rosenthal KS, Zimmerman DH. CEL-1000–-a peptide with adjuvant activity for Th1 immune responses. Vaccine. 2004;22(19):2368–73. PubMed PMID: 15193396. Epub 2004/06/15.
  158. Luster AD. Chemokines--chemotactic cytokines that mediate inflammation. N Engl J Med. 1998 Feb;338(7):436–45. PubMed PMID: 9459648. Epub 1998/02/12.
  159. Rees S, Morrow D, Kenakin T. GPCR drug discovery through the exploitation of allosteric drug binding sites. Receptors Channels. 2002;8(5–6):261–8. PubMed PMID: 12690954. Epub 2003/04/15.
  160. Gether U, Asmar F, Meinild AK, Rasmussen SG. Structural basis for activation of G-protein-coupled receptors. Pharmacol Toxicol. 2002;91(6):304–12. PubMed PMID: 12688373. Epub 2003/04/12.
  161. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996;272(5263):872–7. PubMed PMID: 8629022. Epub 1996/05/10.
  162. Ehrlich HJ, Muller M, Oh HM, Tambyah PA, Joukhadar C, Montomoli E, et al. A clinical trial of a whole-virus H5N1 vaccine derived from cell culture. N Engl J Med. 2008;358(24):2573–84. PubMed PMID: 18550874. Epub 2008/06/14.
  163. Bresson JL, Perronne C, Launay O, Gerdil C, Saville M, Wood J, et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet. 2006;367(9523):1657–64. PubMed PMID: 16714186. Epub 2006/05/23.
  164. Leroux-Roels I, Van der Wielen M, Kafeja F, Vandermeulen C, Lazarus R, Snape MD, et al. Humoral and cellular immune responses to split-virion H5N1 influenza vaccine in young and elderly adults. Vaccine. 2009;27(49):6918–25. PubMed PMID: 19761837. Epub 2009/09/19.
  165. Brady RC, Treanor JJ, Atmar RL, Keitel WA, Edelman R, Chen WH, et al. Safety and immunogenicity of a subvirion inactivated influenza A/H5N1 vaccine with or without aluminum hydroxide among healthy elderly adults. Vaccine. 2009;27(37):5091–5. PubMed PMID: 19577636. Pubmed Central PMCID: 2730950. Epub 2009/07/07.
  166. Keitel WA, Campbell JD, Treanor JJ, Walter EB, Patel SM, He F, et al. Safety and immunogenicity of an inactivated influenza A/H5N1 vaccine given with or without aluminum hydroxide to healthy adults: results of a phase I-II randomized clinical trial. J Infect Dis. 2008;198(9):1309–16. PubMed PMID: 18808338. Pubmed Central PMCID: 3044935. Epub 2008/09/24.
  167. Galli G, Hancock K, Hoschler K, DeVos J, Praus M, Bardelli M, 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 U S A. 2009;106(19):7962–7. PubMed PMID: 19416838. Pubmed Central PMCID: 2674105. Epub 2009/05/07.
  168. Atmar RL, Keitel WA, Patel SM, Katz JM, She D, El Sahly H, et al. Safety and immunogenicity of nonadjuvanted and MF59–adjuvanted influenza A/H9N2 vaccine preparations. Clin Infect Dis. 2006;43(9):1135–42. PubMed PMID: 17029131. Epub 2006/10/10.
  169. Vesikari T, Groth N, Karvonen A, Borkowski A, Pellegrini M. MF59–adjuvanted influenza vaccine (FLUAD) in children: safety and immunogenicity following a second year seasonal vaccination. Vaccine. 2009;27(45):6291–5. PubMed PMID: 19840662. Epub 2009/10/21.
  170. Durando P, Fenoglio D, Boschini A, Ansaldi F, Icardi G, Sticchi L, et al. Safety and immunogenicity of two influenza virus subunit vaccines, with or without MF59 adjuvant, administered to human immunodeficiency virus type 1–seropositive and -seronegative adults. Clin Vaccine Immunol. 2008;15(2):253–9. PubMed PMID: 18003811. Pubmed Central PMCID: 2238067. Epub 2007/11/16.
  171. Vesikari T, Knuf M, Wutzler P, Karvonen A, Kieninger-Baum D, Schmitt HJ, et al. Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med. 2011;365(15):1406–16. PubMed PMID: 21995388. Epub 2011/10/15.
  172. De Bernardis F, Amacker M, Arancia S, Sandini S, Gremion C, Zurbriggen R, et al. A virosomal vaccine against candidal vaginitis: immunogenicity, efficacy and safety profile in animal models. Vaccine. 2012;30(30):4490–8. PubMed PMID: 22561143. Epub 2012/05/09.
  173. Moser C, Amacker M, Zurbriggen R. Influenza virosomes as a vaccine adjuvant and carrier system. Expert Rev Vaccines. 2011;10(4):437–46. PubMed PMID: 21506642. Epub 2011/04/22.
  174. Ambrosch F, Wiedermann G, Jonas S, Althaus B, Finkel B, Gluck R, et al. Immunogenicity and protectivity of a new liposomal hepatitis A vaccine. Vaccine. 1997;15(11):1209–13. PubMed PMID: 9286045. Epub 1997/08/01.
  175. Draper E, Bissett SL, Howell-Jones R, Waight P, Soldan K, Jit M, et al. A randomized, observer-blinded immunogenicity trial of Cervarix((R)) and Gardasil((R)) Human Papillomavirus vaccines in 12–15 year old girls. PLoS One. 2013;8(5):e61825. PubMed PMID: 23650505. Pubmed Central PMCID: 3641072. Epub 2013/05/08.
  176. Hoebe CJ, Vermeiren AP, Dukers-Muijrers NH. Revaccination with Fendrix(R) or HBVaxPro(R) results in better response rates than does revaccination with three doses of Engerix-B(R) in previous non-responders. Vaccine. 2012;30(48):6734–7. PubMed PMID: 22981848. Epub 2012/09/18.
  177. Lehtinen M, Paavonen J, Wheeler CM, Jaisamrarn U, Garland SM, Castellsague X, et al. Overall efficacy of HPV-16/18 AS04–adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4–year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012;13(1):89–99. PubMed PMID: 22075171. Epub 2011/11/15.
  178. Wheeler CM, Castellsague X, Garland SM, Szarewski A, Paavonen J, Naud P, et al. Cross-protective efficacy of HPV-16/18 AS04–adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4–year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012;13(1):100–10. PubMed PMID: 22075170. Epub 2011/11/15.
  179. Leroux-Roels I, Bernhard R, Gerard P, Drame M, Hanon E, Leroux-Roels G. Broad Clade 2 cross-reactive immunity induced by an adjuvanted clade 1 rH5N1 pandemic influenza vaccine. PLoS One. 2008;3(2):e1665. PubMed PMID: 18301743. Pubmed Central PMCID: 2253495. Epub 2008/02/28.
  180. Leroux-Roels I, Roman F, Forgus S, Maes C, De Boever F, Drame M, et al. Priming with AS03 A-adjuvanted H5N1 influenza vaccine improves the kinetics, magnitude and durability of the immune response after a heterologous booster vaccination: an open non-randomised extension of a double-blind randomised primary study. Vaccine. 2010;28(3):849–57. PubMed PMID: 19835828. Epub 2009/10/20.
  181. Powell TJ, Tang J, Derome ME, Mitchell RA, Jacobs A, Deng Y, et al. Plasmodium falciparum synthetic LbL microparticle vaccine elicits protective neutralizing antibody and parasite-specific cellular immune responses. Vaccine. 2013;31(15):1898–904. PubMed PMID: 23481177. Pubmed Central PMCID: 3611586. Epub 2013/03/14.
  182. McNally B, Willette M, Ye F, Partida-Sanchez S, Flano E. Intranasal administration of dsRNA analog poly(I:C) induces interferon-alpha receptor-dependent accumulation of antigen experienced T cells in the airways. PLoS One. 2012;7(12):e51351. PubMed PMID: 23236482. Pubmed Central PMCID: 3517467. Epub 2012/12/14.
  183. Ichinohe T, Ainai A, Tashiro M, Sata T, Hasegawa H. PolyI:polyC12U adjuvant-combined intranasal vaccine protects mice against highly pathogenic H5N1 influenza virus variants. Vaccine. 2009;27(45):6276–9. PubMed PMID: 19840660. Epub 2009/10/21.
  184. Zhou M, Zhang G, Ren G, Gnanadurai CW, Li Z, Chai Q, et al. Recombinant Rabies Viruses Expressing GM-CSF or Flagellin Are Effective Vaccines for Both Intramuscular and Oral Immunizations. PLoS One. 2013;8(5):e63384. PubMed PMID: 23700422. Pubmed Central PMCID: 3658976. Epub 2013/05/24.
  185. Liu G, Song L, Reiserova L, Trivedi U, Li H, Liu X, et al. Flagellin-HA vaccines protect ferrets and mice against H5N1 highly pathogenic avian influenza virus (HPAIV) infections. Vaccine. 2012;30(48):6833–8. PubMed PMID: 23000130. Epub 2012/09/25.
  186. Taylor DN, Treanor JJ, Sheldon EA, Johnson C, Umlauf S, Song L, et al. Development of VAX128, a recombinant hemagglutinin (HA) influenza-flagellin fusion vaccine with improved safety and immune response. Vaccine. 2012;30(39):5761–9. PubMed PMID: 22796139. Epub 2012/07/17.
  187. Burns RP, Jr., Ferbel B, Tomai M, Miller R, Gaspari AA. The imidazoquinolines, imiquimod and R-848, induce functional, but not phenotypic, maturation of human epidermal Langerhans' cells. Clin Immunol. 2000;94(1):13–23. PubMed PMID: 10607486. Epub 1999/12/23.
  188. Shukla NM, Mutz CA, Malladi SS, Warshakoon HJ, Balakrishna R, David SA. Toll-like receptor (TLR)-7 and -8 modulatory activities of dimeric imidazoquinolines. J Med Chem. 2012;55(3):1106–16. PubMed PMID: 22239408. Pubmed Central PMCID: 3276691. Epub 2012/01/14.
  189. Rhee JW, Kim D, Park BK, Kwon S, Cho S, Lee I, et al. Immunization with a hemagglutinin-derived synthetic peptide formulated with a CpG-DNA-liposome complex induced protection against lethal influenza virus infection in mice. PLoS One. 2012;7(11):e48750. PubMed PMID: 23144954. Pubmed Central PMCID: 3492448. Epub 2012/11/13.
  190. Bode C, Zhao G, Steinhagen F, Kinjo T, Klinman DM. CpG DNA as a vaccine adjuvant. Expert Rev Vaccines. 2011;10(4):499–511. PubMed PMID: 21506647. Pubmed Central PMCID: 3108434. Epub 2011/04/22.
  191. Moorthy VS, Ballou WR. Immunological mechanisms underlying protection mediated by RTS,S: a review of the available data. Malar J. 2009;8:312. PubMed PMID: 20042088. Pubmed Central PMCID: 2806383. Epub 2010/01/01.
  192. Garcon N, Heppner DG, Cohen J. Development of RTS,S/AS02: a purified subunit-based malaria vaccine candidate formulated with a novel adjuvant. Expert Rev Vaccines. 2003;2(2):231–8. PubMed PMID: 12899574. Epub 2003/08/06.
  193. Montana M, Verhaeghe P, Ducros C, Terme T, Vanelle P, Rathelot P. Safety review: squalene and thimerosal in vaccines. Therapie. 2010;65(6):533–41. PubMed PMID: 21176760. Epub 2010/12/24.
  194. Christensen D, Agger EM, Andreasen LV, Kirby D, Andersen P, Perrie Y. Liposome-based cationic adjuvant formulations (CAF): past, present, and future. J Liposome Res. 2009;19(1):2–11. PubMed PMID: 19515003. Epub 2009/06/12.
  195. Lingnau K, Riedl K, von Gabain A. IC31 and IC30, novel types of vaccine adjuvant based on peptide delivery systems. Expert Rev Vaccines. 2007;6(5):741–6. PubMed PMID: 17931154. Epub 2007/10/13.
  196. McCluskie MJ, Weeratna RD, Evans DM, Makinen S, Drane D, Davis HL. CpG ODN and ISCOMATRIX adjuvant: a synergistic adjuvant combination inducing strong T-Cell IFN-gamma responses. Biomed Res Int. 2013;2013:636847. PubMed PMID: 23586050. Pubmed Central PMCID: 3618927. Epub 2013/04/16.
  197. Morelli AB, Becher D, Koernig S, Silva A, Drane D, Maraskovsky E. ISCOMATRIX: a novel adjuvant for use in prophylactic and therapeutic vaccines against infectious diseases. J Med Microbiol. 2012;61(Pt 7):935–43. PubMed PMID: 22442293. Epub 2012/03/24.
  198. Vujanic A, Snibson KJ, Wee JL, Edwards SJ, Pearse MJ, Scheerlinck JP, et al. Long-term antibody and immune memory response induced by pulmonary delivery of the influenza Iscomatrix vaccine. Clin Vaccine Immunol. 2012;19(1):79–83. PubMed PMID: 22072721. Pubmed Central PMCID: 3255945. Epub 2011/11/11.
  199. Kulkarni PS, Manjunath K, Agarkhedkar S. Safety and immunogenicity of an adjuvanted whole virion, inactivated A (H1N1) 2009 influenza vaccine in young and elderly adults, and children. Vaccine. 2012;31(1):20–2. PubMed PMID: 23131207. Epub 2012/11/08.
  200. Lin JT, Li CG, Wang X, Su N, Liu Y, Qiu YZ, et al. Antibody persistence after 2–dose priming and booster response to a third dose of an inactivated, adjuvanted, whole-virion H5N1 vaccine. J Infect Dis. 2009;199(2):184–7. PubMed PMID: 19067606. Epub 2008/12/11.
  201. Nolan TM, Richmond PC, Skeljo MV, Pearce G, Hartel G, Formica NT, et al. Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults. Vaccine. 2008;26(33):4160–7. PubMed PMID: 18599164. Epub 2008/07/05.
  202. Nicholson KG, Thompson CI, Klap JM, Wood JM, Batham S, Newman RW, et al. Safety and immunogenicity of whole-virus, alum-adjuvanted whole-virus, virosomal, and whole-virus intradermal influenza A/H9N2 vaccine formulations. Vaccine. 2009;28(1):171–8. PubMed PMID: 19799843. Epub 2009/10/06.
  203. Zhu FC, Wang H, Fang HH, Yang JG, Lin XJ, Liang XF, et al. A novel influenza A (H1N1) vaccine in various age groups. N Engl J Med. 2009;361(25):2414–23. PubMed PMID: 19846844. Epub 2009/10/23.
  204. Nakayama T, Kumagai T, Ishii KJ, Ihara T. Alum-adjuvanted H5N1 whole virion inactivated vaccine (WIV) induced IgG1 and IgG4 antibody responses in young children. Vaccine. 2012;30(52):7662–6. PubMed PMID: 23102974. Epub 2012/10/30.
  205. Ikeno D, Kimachi K, Kino Y, Harada S, Yoshida K, Tochihara S, et al. Immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1, NIBRG-14) vaccine administered by intramuscular or subcutaneous injection. Microbiol Immunol. 2010;54(2):81–8. PubMed PMID: 20377741. Epub 2010/04/10.