• 1
    Ulmer, J. B., Valley, U. and Rappuoli, R., Vaccine manufacturing: challenges and solutions. Nat. Biotechnol. 2006. 24: 13771383.
  • 2
    Mbow, M. L., De Gregorio, E., Valiante, N. M. and Rappuoli, R., New adjuvants for human vaccines. Curr. Opin. Immunol. 2010. 22: 411416.
  • 3
    Carter, D. and Reed, S. G., Role of adjuvants in modeling the immune response. Curr. Opin. HIV AIDS 2010. 5: 409413.
  • 4
    Longhi, M. P., Trumpfheller, C., Idoyaga, J., Caskey, M., Matos, I., Kluger, C., Salazar, al., Dendritic cells require a systemic type I interferon response to induce CD4+ Th1 immunity with poly IC as adjuvant. J. Exp. Med. 2009. 206: 15891602.
  • 5
    Reed, S. G., Bertholet, S., Coler, R. N. and Friede, M., New horizons in adjuvants for vaccine development. Trends Immunol. 2009. 30: 2332.
  • 6
    Mata-Haro, V., Cekic, C., Martin, M., Chilton, P. M., Casella, C. R. and Mitchell, T. C., The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science 2007. 316: 16281632.
  • 7
    Petersen, T., Sika-Paotonu, D., Knight, D., Simkins, H. and Hermans, I., Exploiting the role of endogenous lymphoid-resident dendritic cells in the priming of NKT cells and CD8+ T cells to dendritic cell-based vaccines. PLoS One 2011. 6: e17657.
  • 8
    Bal, S., Hortensius, S., Ding, Z., Jiskoot, W. and Bouwstra, J., Co-encapsulation of antigen and Toll-like receptor ligand in cationic liposomes affects the quality of the immune response in mice after intradermal vaccination. Vaccine 2011. 29: 10451052.
  • 9
    Moriya, K., Wakabayashi, A., Shimizu, M., Tamura, H., Dan, K. and Takahashi, H., Induction of tumor-specific acquired immunity against already established tumors by selective stimulation of innate DEC-205+ dendritic cells. Cancer Immunol. Immunother. 2010. 59: 10831095.
  • 10
    Prajeeth, C. K., Jirmo, A. C., Krishnaswamy, J. K., Ebensen, T., Guzman, C. A., Weiss, S., Constabel, H. et al., The synthetic TLR2 agonist BPPcysMPEG leads to efficient cross-priming against co-administered and linked antigens. Eur. J. Immunol. 2010. 40: 12721283.
  • 11
    MacLeod, M. K. L., McKee, A. S., David, A., Wang, J., Mason, R., Kappler, J. W. and Marrack, P., Vaccine adjuvants aluminum and monophosphoryl lipid A provide distinct signals to generate protective cytotoxic memory CD8 T cells. Proc. Natl. Acad. Sci. USA 2011. 108: 79147919.
  • 12
    Zhu, Q., Egelston, C., Vivekanandhan, A., Uematsu, S., Akira, S., Klinman, D. M., Belyakov, I. M. and Berzofsky, J. A., Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: Implications for vaccines. Proc. Natl. Acad. Sci. USA 2008. 105: 1626016265.
  • 13
    Joffre, O., Nolte, M. A., Sporri, R. and Reis e Sousa, C., Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol. Rev. 2009. 227: 234247.
  • 14
    Mazzoni, A. and Segal, D. M., Controlling the toll road to dendritic cell polarization. J. Leukoc. Biol. 2004. 75: 721730.
  • 15
    Banchereau, J. and Steinman, R. M., Dendritic cells and the control of immunity. Nature 1998. 392: 245252.
  • 16
    Idoyaga, J., Suda, N., Suda, K., Park, C. G. and Steinman, R. M., Antibody to Langerin/CD207 localizes large numbers of CD8α+ dendritic cells to the marginal zone of mouse spleen. Proc. Natl. Acad. Sci. USA 2009. 106: 15241529.
  • 17
    Steinhagen, F., Kinjo, T., Bode, C. and Klinman, D. M., TLR-based immune adjuvants. Vaccine 2010. 29: 33413355.
  • 18
    Thompson, B. S., Chilton, P. M., Ward, J. R., Evans, J. T. and Mitchell, T. C., The low-toxicity versions of LPS, MPL adjuvant and RC529, are efficient adjuvants for CD4+ T cells. J. Leukoc. Biol. 2005. 78: 12731280.
  • 19
    Aguilar, J. C. and Rodriguez, E. G., Vaccine adjuvants revisited. Vaccine 2007. 25: 37523762.
  • 20
    Baldridge, J. R. and Crane, R. T., Monophosphoryl lipid A (MPL) formulations for the next generation of vaccines. Methods 1999. 19: 103107.
  • 21
    Dubensky, T. W., Jr., and Reed, S. G., Adjuvants for cancer vaccines. Semin. Immunol. 2010. 22: 155161.
  • 22
    Monie, A., Hung, C. F., Roden, R. and Wu, T. C., Cervarix: a vaccine for the prevention of HPV 16, 18-associated cervical cancer. Biologics 2008. 2: 97105.
  • 23
    Szarewski, A., HPV vaccine: Cervarix. Exp. Opin. Biol. Ther. 2010. 10: 477487.
  • 24
    Ismaili, J., Rennesson, J., Aksoy, E., Vekemans, J., Vincart, B., Amraoui, Z., Van Laethem, F. et al., Monophosphoryl lipid A activates both human dendritic cells and T cells. J. Immunol. 2002. 168: 926932.
  • 25
    Didierlaurent, A. M., Morel, S., Lockman, L., Giannini, S. L., Bisteau, M., Carlsen, H., Kielland, A. et al., AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J. Immunol. 2009. 183: 61866197.
  • 26
    Trumpfheller, C., Caskey, M., Nchinda, G., Longhi, M. P., Mizenina, O., Huang, Y., Schlesinger, S. J. et al., The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc. Natl. Acad. Sci. USA 2008. 105: 25742579.
  • 27
    Baldwin, S. L., Shaverdian, N., Goto, Y., Duthie, M. S., Raman, V. S., Evers, T., Mompoint, F. et al., Enhanced humoral and Type 1 cellular immune responses with Fluzone adjuvanted with a synthetic TLR4 agonist formulated in an emulsion. Vaccine 2009. 27: 59565963.
  • 28
    Coler, R. N., Baldwin, S. L., Shaverdian, N., Bertholet, S., Reed, S. J., Raman, V. S., Lu, X. et al., A synthetic adjuvant to enhance and expand immune responses to influenza vaccines. PLoS One 2010. 5: e13677.
  • 29
    Perrie, Y., Mohammed, A. R., Kirby, D. J., McNeil, S. E. and Bramwell, V. W., Vaccine adjuvant systems: enhancing the efficacy of sub-unit protein antigens. Int. J. Pharm. 2008. 364: 272280.
  • 30
    Bonifaz, L. C., Bonnyay, D. P., Charalambous, A., Darguste, D. I., Fujii, S., Soares, H., Brimnes, M. K. et al., In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J. Exp. Med. 2004. 199: 815824.
  • 31
    Steinman, R. M., Dendritic cells in vivo: a key target for a new vaccine science. Immunity 2008. 29: 319324.
  • 32
    Thoelen, S., Van Damme, P., Mathei, C., Leroux-Roels, G., Desombere, I., Safary, A., Vandepapeliere, P. et al., Safety and immunogenicity of a hepatitis B vaccine formulated with a novel adjuvant system. Vaccine 1998. 16: 708714.
  • 33
    Bojang, K. A., Olodude, F., Pinder, M., Ofori-Anyinam, O., Vigneron, L., Fitzpatrick, S., Njie, F. et al., Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children. Vaccine 2005. 23: 41484157.
  • 34
    Hirschfeld, M., Ma, Y., Weis, J. H., Vogel, S. N. and Weis, J. J., Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J. Immunol. 2000. 165: 618622.
  • 35
    Tapping, R. I., Akashi, S., Miyake, K., Godowski, P. J. and Tobias, P. S., Toll-like receptor 4, but not toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides. J. Immunol. 2000. 165: 57805787.
  • 36
    Jung, S., Unutmaz, D., Wong, P., Sano, G., De los Santos, K., Sparwasser, T., Wu, S. et al., In vivo depletion of CD11c+ dendritic cells abrogation priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 2002. 17: 211220.
  • 37
    Salomon, B. and Bluestone, J. A., Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu. Rev. Immunol. 2001. 19: 225252.
  • 38
    Bleharski, J. R., Niazi, K. R., Sieling, P. A., Cheng, G. and Modlin, R. L., Signaling lymphocytic activation molecule is expressed on CD40 ligand- activated dendritic cells and directly augments production of inflammatory cytokines. J. Immunol. 2001. 167: 31743181.
  • 39
    Moser, M. and Murphy, K. M., Dendritic cell regulation of TH1-TH2 development. Nat. Immunol. 2000. 1: 199205.
  • 40
    Fujii, S., Liu, K., Smith, C., Bonito, A. J. and Steinman, R. M., The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J. Exp. Med. 2004. 199: 16071618.
  • 41
    Pulendran, B., Modulating vaccine reponses with dendritic cells and toll-like receptors. Immunol. Rev. 2004. 199: 227250.
  • 42
    Steinman, R. M. and Hemmi, H., Dendritic cells: translating innate to adaptive immunity. Curr. Top. Microbiol. Immunol. 2006. 311: 1758.
  • 43
    Coler, R. N., Bertholet, S., Moutaftsi, M., Guderian, J. A., Windish, H. P., Baldwin, S. L., Laughlin, E. M. et al., Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant. PLoS One 2011. 6: e16333.
  • 44
    Hansen, S. G., Vieville, C., Whizin, N., Coyne-Johnson, L., Siess, D. C., Drummond, D. D., Legasse, A. W. et al., Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat. Med. 2009. 15: 293299.
  • 45
    Rerks-Ngarm, S., Pitisuttithum, P., Nitayaphan, S., Kaewkungwal, J., Chiu, J., Paris, R., Premsri, N. et al., Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 2009. 361: 22092220.
  • 46
    Brenchley, J. M., Schacker, T. W., Ruff, L. E., Price, D. A., Taylor, J. H., Beilman, G. J., Nguyen, P. L. et al., CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J. Exp. Med. 2004. 200: 749759.
  • 47
    Mehandru, S., Poles, M. A., Tenner-Racz, K., Horowitz, A., Hurley, A., Hogan, C., Boden, D. et al., Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J. Exp. Med. 2004. 200: 761770.
  • 48
    Nchinda, G., Amadu, D., Trumpfheller, C., Mizenina, O., Uberla, K. and Steinman, R. M., Dendritic cell targeted HIV gag protein vaccine provides help to a DNA vaccine including mobilization of protective CD8+ T cells. Proc. Natl. Acad. Sci. USA 2010. 107: 42814286.
  • 49
    Nakanishi, Y., Lu, B., Gerard, C. and Iwasaki, A., CD8+T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 2009. 462: 510513.
  • 50
    Belyakov, I. M., Isakov, D., Zhu, Q., Dzutsev, A. and Berzofsky, J. A., A novel functional CTL avidity/activity compartmentalization to the site of mucosal immunization contributes to protection of macaques against simian/human immunodeficiency viral depletion of mucosal CD4+ T cells. J. Immunol. 2007. 178: 72117221.
  • 51
    Kaul, R., Plummer, F. A., Kimani, J., Dong, T., Kiama, P., Rostron, T., Njagi, E. et al., HIV-1-specific mucosal CD8+ lymphocyte responses in the cervix of HIV-1-resistant prostitutes in Nairobi. J. Immunol. 2000. 164: 16021611.
  • 52
    Baba, T. W., Liska, V., Hofmann-Lehmann, R., Vlasak, J., Xu, W., Ayehunie, S., Cavacini, L. A. et al., Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat. Med. 2000. 6: 200206.
  • 53
    Kozlowski, P., Cu-Uvin, S., Neutra, M. and Flanigan, T., Comparison of the oral, rectal, and vaginal immunization routes for induction of antibodies in rectal and genital tract secretions of women. Infect. Immun. 1997. 65: 13871394.
  • 54
    Belyakov, I. M., Hel, Z., Kelsall, B., Kuznetsov, V. A., Ahlers, J. D., Nacsa, J., Watkins, D. I. et al., Mucosal AIDS vaccine reduces disease and viral load in gut reservoir and blood after mucosal infection of macaques. Nat. Med. 2001. 7: 13201326.
  • 55
    Belyakov, I. M., Ahlers, J. D., Nabel, G. J., Moss, B. and Berzofsky, J. A., Generation of functionally active HIV-1 specific CD8+ CTL in intestinal mucosa following mucosal, systemic or mixed prime-boost immunization. Virology 2008. 381: 106115.
  • 56
    Bertholet, S., Ireton, G. C., Ordway, D. J., Windish, H. P., Pine, S. O., Kahn, M., Phan, T. et al., A defined tuberculosis vaccine candidate boosts BCG and protects against multidrug-resistant Mycobacterium tuberculosis. Sci. Transl. Med. 2010. 2: 53ra74.
  • 57
    Martinez, V., Costagliola, D., Bonduelle, O., N'Go, N., Schnuriger, A., Théodorou, I., Clauvel, J. et al., Combination of HIV-1–specific CD4 Th1 cell responses and IgG2 antibodies is the best predictor for persistence of long-term nonprogression. J. Infect. Dis. 2005. 191: 20532063.
  • 58
    French, M. A., Vaccine-induced IgG2 anti-HIV p24 is associated with control of HIV in patients with a ‘high-affinity’ FcRIIa genotype. AIDS 2010. 24: 19831990.
  • 59
    Lofthouse, S., Immunological aspects of controlled antigen delivery. Adv. Drug Deliv. Rev. 2002. 54: 863870.
  • 60
    Mosca, F., Tritto, E., Muzzi, A., Monaci, E., Bagnoli,F., Iavarone, C., O'Hagan, D. et al., Molecular and cellular signatures of human vaccine adjuvants. Proc. Natl. Acad. Sci. USA 2008. 105: 1050110506.
  • 61
    Reed, S., Bertholet, S., Coler, R. and Friede, M., New horizons in adjuvants for vaccine development. Trends Immunol. 2009. 30: 2332.