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Enhancement of Infectious Disease Vaccines Through TLR9-Dependent Recognition of CpG DNA

  • Chapter
From Innate Immunity to Immunological Memory

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 311))

Abstract

The adaptive immune system—with its remarkable ability to generate antigen-specific antibodies and T lymphocytes against pathogens never before “seen” by an organism—is one of the marvels of evolution. However, to generate these responses, the adaptive immune system requires activation by the innate immune system. Toll-like receptors (TLRs) are perhaps the best-understood family of innate immune receptors for detecting infections and stimulating adaptive immune responses. TLR9 appears to have evolved to recognize infections by a subtle structural difference between eukaryotic and prokaryotic/viral DNA; only the former frequently methylates CpG dinucleotides. Used as vaccine adjuvants, synthetic oligodeoxynucleotide (ODN) ligands for TLR9—CpG ODN—greatly enhance the speed and strength of the immune responses to vaccination.

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References

  1. Pulendran B (2005) Variegation of the immune response with dendritic cells and pathogen recognition receptors. J Immunol 174:2457–2465

    PubMed  CAS  Google Scholar 

  2. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745

    PubMed  CAS  Google Scholar 

  3. Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, Hood LE, Aderem A (2005) The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 102:9577–9582

    PubMed  CAS  Google Scholar 

  4. Rankin R, Pontarollo R, Ioannou X, Krieg AM, Hecker R, Babiuk LA, van Drunen Littel-van den Hurk S (2001) CpG motif identification for veterinary and laboratory species demonstrates that sequence recognition is highly conserved. Antisense Nucleic Acid Drug Dev 11:333–340

    PubMed  CAS  Google Scholar 

  5. Hemmi H, Kaisho T, Takeda K, Akira S (2003) The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol 170:3059–3064

    PubMed  CAS  Google Scholar 

  6. Vollmer J, Weeratna RD, Jurk M, Samulowitz U, McCluskie MJ, Payette P, Davis HL, Schetter C, Krieg AM (2004) Oligodeoxynucleotides lacking CpG dinucleotides mediate Toll-like receptor 9 dependent T helper type 2 biased immune stimulation. Immunology 113:212–223

    PubMed  CAS  Google Scholar 

  7. Yasuda K, Yu P, Kirschning CJ, Schlatter B, Schmitz F, Heit A, Bauer S, Hochrein H, Wagner H (2005) Endosomal translocation of vertebrate DNA activates dendritic cells via TLR9-dependent and-independent pathways. J Immunol 174:6129–6136

    PubMed  CAS  Google Scholar 

  8. Spies B, Hochrein H, Vabulas M, Huster K, Busch DH, Schmitz F, Heit A, Wagner H (2003) Vaccination with plasmid DNA activates dendritic cells via Toll-like receptor 9 (TLR9) but functions in TLR9-deficient mice. J Immunol 171:5908–5912

    PubMed  CAS  Google Scholar 

  9. Babiuk S, Mookherjee N, Pontarollo R, Griebel P, van Drunen Littel-van den Hurk S, Hecker R, Babiuk L (2004) TLR9-/-and TLR9+/+ mice display similar immune responses to a DNA vaccine. Immunology 113:114–120

    PubMed  CAS  Google Scholar 

  10. Tudor D, Dubuquoy C, Gaboriau V, Lefevre F, Charley B, Riffault S (2005) TLR9 pathway is involved in adjuvant effects of plasmid DNA-based vaccines. Vaccine 23:1258–1264

    PubMed  CAS  Google Scholar 

  11. Ishii KJ, Suzuki K, Coban C, Takeshita F, Itoh Y, Matoba H, Kohn LD, Klinman DM (2001) Genomic DNA released by dying cells induces the maturation of APCs. J Immunol 167:2602–2607

    PubMed  CAS  Google Scholar 

  12. Krieg AM (2002) CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20:709–760

    PubMed  CAS  Google Scholar 

  13. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995

    PubMed  CAS  Google Scholar 

  14. Hayashi F, Means TK, Luster AD (2003) Toll-like receptors stimulate human neutrophil function. Blood 102:2660–2669

    PubMed  CAS  Google Scholar 

  15. Li J, Ma Z, Tang ZL, Stevens T, Pitt B, Li S (2004) CpG DNA-mediated immune response in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 287:L552–L558

    PubMed  CAS  Google Scholar 

  16. Platz J, Beisswenger C, Dalpke A, Koczulla R, Pinkenburg O, Vogelmeier C, Bals R (2004) Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J Immunol 173:1219–1223

    PubMed  CAS  Google Scholar 

  17. Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549

    PubMed  CAS  Google Scholar 

  18. Yi AK, Chang M, Peckham DW, Krieg AM, Ashman RF (1998) CpG oligodeoxyri-bonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry [published erratum appears in J Immunol 1999 Jul 15;163(2):1093]. J Immunol 160:5898–5906

    PubMed  CAS  Google Scholar 

  19. Hartmann G, Krieg AM (2000) Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol 164:944–953

    PubMed  CAS  Google Scholar 

  20. Brown WC, Estes DM, Chantler SE, Kegerreis KA, Suarez CE (1998) DNA and a CpG oligonucleotide derived from Babesia bovis aremitogenic for bovine B cells. Infect Immun 66:5423–5432

    PubMed  CAS  Google Scholar 

  21. Ballas ZK, Rasmussen WL, Krieg AM (1996) Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J Immunol 157:1840–1845

    PubMed  CAS  Google Scholar 

  22. Hartmann G, Weeratna RD, Ballas ZK, Payette P, Blackwell S, Suparto I, Rasmussen WL, Waldschmidt M, Sajuthi D, Purcell RH, Davis HL, Krieg AM (2000) Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 164:1617–1624

    PubMed  CAS  Google Scholar 

  23. Pisetsky DS, Reich CF 3rd (1998) The influence of base sequence on the immunological properties of defined oligonucleotides. Immunopharmacology 40:199–208

    PubMed  CAS  Google Scholar 

  24. Roberts TL, Sweet MJ, Hume DA, Stacey KJ (2005) Cutting edge: species-specific TLR9-mediated recognition of CpG and non-CpG phosphorothioate-modified oligonucleotides. J Immunol 174:605–608

    PubMed  CAS  Google Scholar 

  25. Krug A, Rothenfusser S, Hornung V, Jahrsdorfer B, Blackwell S, Ballas ZK, Endres S, Krieg AM, Hartmann G (2001) Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells. Eur J Immunol 31:2154–2163

    PubMed  CAS  Google Scholar 

  26. Vollmer J, Weeratna R, Payette P, Jurk M, Schetter C, Laucht M, Wader T, Tluk S, Liu M, Davis HL, Krieg AM (2004) Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur J Immunol 34:251–262

    PubMed  CAS  Google Scholar 

  27. Hartmann G, Battiany J, Poeck H, Wagner M, Kerkmann M, Lubenow N, Rothenfusser S, Endres S (2003) Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells. Eur J Immunol 33:1633–1641

    PubMed  CAS  Google Scholar 

  28. Marshall JD, Fearon K, Abbate C, Subramanian S, Yee P, Gregorio J, Coffman RL, Van Nest G (2003) Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions. J Leukoc Biol 73:781–792

    PubMed  CAS  Google Scholar 

  29. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A, Taya C, Taniguchi T (2005) Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035–1040

    PubMed  CAS  Google Scholar 

  30. Krieg AM (1995) Uptake and localization of phosphodiester and chimeric oligodeoxynucleotides in normal and leukemic primary cells. In: Akhtar S (ed) Delivery strategies for antisense oligonucleotide therapeutics. CRC Press, Boca Raton, pp 177–190

    Google Scholar 

  31. Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, Lien E, Nilsen NJ, Espevik T, Golenbock DT (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 5:190–198

    PubMed  CAS  Google Scholar 

  32. Rutz M, Metzger J, Gellert T, Luppa P, Lipford GB, Wagner H, Bauer S (2004) Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence-and pH-dependent manner. Eur J Immunol 34:2541–2550

    PubMed  CAS  Google Scholar 

  33. Yi AK, Tuetken R, Redford T, Waldschmidt M, Kirsch J, Krieg AM (1998) CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J Immunol 160:4755–4761

    PubMed  CAS  Google Scholar 

  34. Ahmad-Nejad P, Hacker H, Rutz M, Bauer S, Vabulas RM, Wagner H (2002) Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur J Immunol 32:1958–1968

    PubMed  CAS  Google Scholar 

  35. Hacker H, Mischak H, Miethke T, Liptay S, Schmid R, Sparwasser T, Heeg K, Lipford GB, Wagner H (1998) CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J 17:6230–6240

    PubMed  CAS  Google Scholar 

  36. Manzel L, Strekowski L, Ismail FM, Smith JC, Macfarlane DE (1999) Antagonism of immunostimulatory CpG-oligodeoxy nucleotides by 4-aminoquinolines and other weak bases: mechanistic studies. J Pharmacol Exp Ther 291:1337–1347

    PubMed  CAS  Google Scholar 

  37. Ishii KJ, Takeshita F, Gursel I, Gursel M, Conover J, Nussenzweig A, Klinman DM (2002) Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation. J Exp Med 196:269–274

    PubMed  CAS  Google Scholar 

  38. Hacker H, Vabulas RM, Takeuchi O, Hoshino K, Akira S, Wagner H (2000) Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J Exp Med 192:595–600

    PubMed  CAS  Google Scholar 

  39. Schnare M, Holt AC, Takeda K, Akira S, Medzhitov R (2000) Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr Biol 10:1139–1142

    PubMed  CAS  Google Scholar 

  40. Muzio M, Ni J, Feng P, Dixit VM (1997) IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278:1612–1615

    PubMed  CAS  Google Scholar 

  41. Muzio M, Natoli G, Saccani S, Levrero M, Mantovani A (1998) The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J Exp Med 187:2097–2101

    PubMed  CAS  Google Scholar 

  42. Yi AK, Krieg AM (1998) Rapid induction of mitogen-activated protein kinases by immune stimulatory CpG DNA. J Immunol 161:4493–4497

    PubMed  CAS  Google Scholar 

  43. Takeshita F, Klinman DM (2000) CpG ODN-mediated regulation of IL-12 p40 transcription. Eur J Immunol 30:1967–1976

    PubMed  CAS  Google Scholar 

  44. Tsujimura H, Tamura T, Kong HJ, Nishiyama A, Ishii KJ, Klinman DM, Ozato K (2004) Toll-like receptor 9 signaling activates NF-kappaB through IFN regulatory factor-8/IFN consensus sequence binding protein in dendritic cells. J Immunol 172:6820–6827

    PubMed  CAS  Google Scholar 

  45. Choudhury BK, Wild JS, Alam R, Klinman DM, Boldogh I, Dharajiya N, Mileski WJ, Sur S (2002) In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma. J Immunol 169:5955–5961

    PubMed  CAS  Google Scholar 

  46. Yi AK, Yoon JG, Krieg AM (2003) Convergence of CpG DNA-and BCR-mediated signals at the c-Jun N-terminal kinase and NF-kappaB activation pathways: regulation by mitogen-activated protein kinases. Int Immunol 15:577–591

    PubMed  CAS  Google Scholar 

  47. Yi AK, Yoon JG, Yeo SJ, Hong SC, English BK, Krieg AM (2002) Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J Immunol 168:4711–4720

    PubMed  CAS  Google Scholar 

  48. Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, Takeuchi O, Akira S (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5:1061–1068

    PubMed  CAS  Google Scholar 

  49. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, Takeuchi O, Akira S (2005) Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7-and TLR9-mediated interferon-alpha induction. J Exp Med 201:915–923

    PubMed  CAS  Google Scholar 

  50. Yeo SJ, Yoon JG, Yi AK (2003) Myeloid differentiation factor 88-dependent posttranscriptional regulation of cyclooxygenase-2 expression by CpG DNA: tumor necrosis factor-alpha receptor-associated factor 6, a diverging point in the Toll-like receptor 9-signaling. J Biol Chem 278:40590–40600

    PubMed  CAS  Google Scholar 

  51. Yeo SJ, Gravis D, Yoon JG, Yi AK (2003) Myeloid differentiation factor 88-dependent transcriptional regulation of cyclooxygenase-2 expression by CpG DNA: role of NF-kappaB and p38. J Biol Chem 278:22563-22573

    Google Scholar 

  52. Asselin-Paturel C, Brizard G, Chemin K, Boonstra A, O’Garra A, Vicari A, Trinchieri G (2005) Type I interferon dependence of plasmacytoid dendritic cell activation and migration. J Exp Med 201:1157–1167

    PubMed  CAS  Google Scholar 

  53. Sun CM, Deriaud E, Leclerc C, Lo-Man R (2005) Upon TLR9 signaling, CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs. Immunity 22:467–477

    PubMed  CAS  Google Scholar 

  54. Duramad O, Fearon KL, Chan JH, Kanzler H, Marshall JD, Coffman RL, Barrat FJ (2003) IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 102:4487–4492

    PubMed  CAS  Google Scholar 

  55. Vicari AP, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, Merle P, Colombo MP, O’Garra A, Trinchieri G, Caux C (2002) Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 196:541–549

    PubMed  CAS  Google Scholar 

  56. Cole AM, Ganz T, Liese AM, Burdick MD, Liu L, Strieter RM (2001) Cutting edge: IFN-inducible ELR-CXC chemokines display defensin-like antimicrobial activity. J Immunol 167:623–627

    PubMed  CAS  Google Scholar 

  57. Salazar-Mather TP, Hamilton TA, Biron CA (2000) A chemokine-to-cytokine-tochemokine cascade critical in antiviral defense. J Clin Invest 105:985–993

    PubMed  CAS  Google Scholar 

  58. Liu MT, Chen BP, Oertel P, Buchmeier MJ, Armstrong D, Hamilton TA, Lane TE (2000) The T cell chemoattractant IFN-inducible protein 10 is essential in host defense against viral-induced neurologic disease. J Immunol 165:2327–2330

    PubMed  CAS  Google Scholar 

  59. Mahalingam S, Farber JM, Karupiah G (1999) The interferon-inducible chemokines MuMig and Crg-2 exhibit antiviral activity In vivo. J Virol 73:1479–1491

    PubMed  CAS  Google Scholar 

  60. Tannenbaum CS, Tubbs R, Armstrong D, Finke JH, Bukowski RM, Hamilton TA (1998) The CXC chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor. J Immunol 161:927–932

    PubMed  CAS  Google Scholar 

  61. Narvaiza I, Mazzolini G, Barajas M, Duarte M, Zaratiegui M, Qian C, Melero I, Prieto J (2000) Intratumoral coinjection of two adenoviruses, one encoding the chemokine IFN-gamma-inducible protein-10 and another encoding IL-12, results in marked antitumoral synergy. J Immunol 164:3112–3122

    PubMed  CAS  Google Scholar 

  62. Pertl U, Luster AD, Varki NM, Homann D, Gaedicke G, Reisfeld RA, Lode HN (2001) IFN-gamma-inducible protein-10 is essential for the generation of a protective tumor-specific CD8 T cell response induced by single-chain IL-12 gene therapy. J Immunol 166:6944–6951

    PubMed  CAS  Google Scholar 

  63. Weighardt H, Feterowski C, Veit M, Rump M, Wagner H, Holzmann B (2000) Increased resistance against acute polymicrobial sepsis in mice challenged with immunostimulatory CpG oligodeoxynucleotides is related to an enhanced innate effector cell response. J Immunol 165:4537–4543

    PubMed  CAS  Google Scholar 

  64. Utaisincharoen P, Kespichayawattana W, Anuntagool N, Chaisuriya P, Pichyangkul S, Krieg AM, Sirisinha S (2003) CpG ODN enhances uptake of bacteria by mouse macrophages. Clin Exp Immunol 132:70–75

    PubMed  CAS  Google Scholar 

  65. Klinman DM, Currie D, Gursel I, Verthelyi D (2004) Use of CpG oligodeoxynucleotides as immunoprotective agents. Expert Opin Biol Ther 4:937–946

    PubMed  CAS  Google Scholar 

  66. Kemp TJ, Elzey BD, Griffith TS (2003) Plasmacytoid dendritic cell-derived IFN-alpha induces TNF-related apoptosis-inducing ligand/Apo-2L-mediated antitumor activity by human monocytes following CpG oligodeoxynucleotide stimulation. J Immunol 171:212–218

    PubMed  CAS  Google Scholar 

  67. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603–607

    PubMed  CAS  Google Scholar 

  68. Liu YJ (2005) IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 23:275–306

    PubMed  CAS  Google Scholar 

  69. Pulendran B (2004) Modulating vaccine responses with dendritic cells and Toll-like receptors. Immunol Rev 199:227–250

    PubMed  CAS  Google Scholar 

  70. Moseman EA, Liang XQ, Dawson AJ, Panoskaltsis-Mortari A, Krieg AM, Liu YJ, Blazar BR, Chen W (2004) Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol 173:4433–4442

    PubMed  CAS  Google Scholar 

  71. Rothenfusser S, Tuma E, Endres S, Hartmann G (2002) Plasmacytoid dendritic cells: the key to CpG. Hum Immunol 63:1111–1119

    PubMed  CAS  Google Scholar 

  72. Rothenfusser S, Hornung V, Ayyoub M, Britsch S, Towarowski A, Krug A, Sarris A, Lubenow N, Speiser D, Endres S, Hartmann G (2004) CpG-A and CpG-B oligonucleotides differentially enhance human peptide-specific primary and memory CD8+ T-cell responses in vitro. Blood 103:2162–2169

    PubMed  CAS  Google Scholar 

  73. Sparwasser T, Vabulas RM, Villmow B, Lipford GB, Wagner H (2000) Bacterial CpG-DNA activates dendritic cells in vivo: T helper cell-independent cytotoxic T cell responses to soluble proteins. Eur J Immunol 30:3591–3597

    PubMed  CAS  Google Scholar 

  74. Davis HL, Weeratna R, Waldschmidt TJ, Tygrett L, Schorr J, Krieg AM (1998) CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen [published erratumappears in J Immunol 1999 Mar 1;162(5):3103]. J Immunol 160:870–876

    PubMed  CAS  Google Scholar 

  75. He B, Qiao X, Cerutti A (2004) CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J Immunol 173:4479–4491

    PubMed  CAS  Google Scholar 

  76. Lipford GB, Sparwasser T, Zimmermann S, Heeg K, Wagner H (2000) CpG-DNAmediated transient lymphadenopathy is associated with a state of Th1 predisposition to antigen-driven responses. J Immunol 165:1228–1235

    PubMed  CAS  Google Scholar 

  77. Chu RS, McCool T, Greenspan NS, Schreiber JR, Harding CV (2000) CpG oligodeoxynucleotides act as adjuvants for pneumococcal polysaccharide-protein conjugate vaccines and enhance antipolysaccharide immunoglobulin G2a (IgG2a) and IgG3 antibodies. Infect Immun 68:1450–1456

    PubMed  CAS  Google Scholar 

  78. Kovarik J, Bozzotti P, Tougne C, Davis HL, Lambert PH, Krieg AM, Siegrist CA (2001) Adjuvant effects of CpG oligodeoxynucleotides on responses against T-independent type 2 antigens. Immunology 102:67–76

    PubMed  CAS  Google Scholar 

  79. von Hunolstein C, Teloni R, Mariotti S, Recchia S, Orefici G, Nisini R (2000) Synthetic oligodeoxynucleotide containingCpGmotif induces ananti-polysaccharide type 1-like immune response after immunization of mice with Haemophilus in-fluenzae type b conjugate vaccine. Int Immunol 12:295–303

    Google Scholar 

  80. Tighe H, Takabayashi K, Schwartz D, Marsden R, Beck L, Corbeil J, Richman DD, Eiden JJ Jr, Spiegelberg HL, Raz E (2000) Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity. Eur J Immunol 30:1939–1947

    PubMed  CAS  Google Scholar 

  81. Hartmann E, Wollenberg B, Rothenfusser S, Wagner M, Wellisch D, Mack B, Giese T, Gires O, Endres S, Hartmann G (2003) Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res 63:6478–6487

    PubMed  CAS  Google Scholar 

  82. Kim SK, Ragupathi G, Musselli C, Choi SJ, Park YS, Livingston PO (2000) Comparison of the effect of different immunological adjuvants on the antibody and T-cell response to immunization with MUC1-KLH and GD3-KLH conjugate cancer vaccines. Vaccine 18:597–603

    Google Scholar 

  83. Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV (1997) CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J Exp Med 186:1623–1631

    PubMed  CAS  Google Scholar 

  84. Lipford GB, Bauer M, Blank C, Reiter R, Wagner H, Heeg K (1997) CpG-containing synthetic oligonucleotides promote B and cytotoxic T cell responses to protein antigen: a new class of vaccine adjuvants. Eur J Immunol 27:2340–2344

    PubMed  CAS  Google Scholar 

  85. Roman M, Martin-Orozco E, Goodman JS, Nguyen MD, Sato Y, Ronaghy A, Kornbluth RS, Richman DD, Carson DA, Raz E (1997) Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants [see comments]. Nat Med 3:849–854

    PubMed  CAS  Google Scholar 

  86. Zwaveling S, Mota SCF, Nouta J, Johnson M, Lipford GB, Offringa R, van der Burg SH, Melief CJM (2002) Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides. J Immunol 169:350–358

    PubMed  CAS  Google Scholar 

  87. Davis HL (2000) Use of CpG DNA for enhancing specific immune responses. Curr Top Microbiol Immunol 247:171–183

    PubMed  CAS  Google Scholar 

  88. Kim SK, Ragupathi G, Cappello S, Kagan E, Livingston PO (2001) Effect of immunological adjuvant combinations on the antibody and T-cell response to vaccination with MUC1-KLH and GD3-KLH conjugates. Vaccine 19:530–537

    Google Scholar 

  89. Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM (1989) Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression ofmurine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med 169:59–72

    PubMed  CAS  Google Scholar 

  90. Sher A (1992) Schistosomiasis. Parasitizing the cytokine system. Nature 356:565–566

    PubMed  CAS  Google Scholar 

  91. Chisari FV, Ferrari C (1995) Hepatitis B virus immunopathogenesis. Annu Rev Immunol 13:29–60

    PubMed  CAS  Google Scholar 

  92. World Health Organization (2001) Global Alliance for Vaccines and Immunization (GAVI). Fact Sheet No. 169

    Google Scholar 

  93. Freidag BL, Melton GB, Collins F, Klinman DM, Cheever A, Stobie L, Suen W, Seder RA (2000) CpG oligodeoxynucleotides and interleukin-12 improve the efficacy of Mycobacterium bovis BCG vaccination in mice challenged with M. tuberculosis. Infect Immun 68:2948–2953

    PubMed  CAS  Google Scholar 

  94. Jones TR, Obaldia N 3rd, Gramzinski RA, Charoenvit Y, Kolodny N, Kitov S, Davis HL, Krieg AM, Hoffman SL (1999) Synthetic oligodeoxynucleotides containing CpG motifs enhance immunogenicity of a peptide malaria vaccine in Aotus monkeys. Vaccine 17:3065–3071

    PubMed  CAS  Google Scholar 

  95. Walker PS, Scharton-Kersten T, Krieg AM, Love-Homan L, Rowton ED, Udey MC, Vogel JC (1999) Immunostimulatory oligodeoxynucleotides promote protective immunity and provide systemic therapy for leishmaniasis via IL-12-and IFN-γ-dependent mechanisms. Proc Natl Acad Sci U S A 96:6970–6975

    PubMed  CAS  Google Scholar 

  96. Eastcott JW, Holmberg CJ, Dewhirst FE, Esch TR, Smith DJ, Taubman MA (2001) Oligonucleotide containing CpG motifs enhances immune response tomucosally or systemically administered tetanus toxoid. Vaccine 19:1636–1642

    PubMed  CAS  Google Scholar 

  97. Leelawongtawon R, Somroop S, Chaisri U, Tongtawe P, Chongsa-nguan M, Kalambaheti T, Tapchaisri P, Pichyangkul S, Sakolvaree Y, Kurazono H, Hayashi H, Chaicumpa W (2003) CpG DNA, liposome and refined antigen oral cholera vaccine. Asian Pac J Allergy Immunol 21:231–239

    PubMed  CAS  Google Scholar 

  98. Nesburn AB, Ramos TV, Zhu X, Asgarzadeh H, Nguyen V, BenMohamed L (2005) Local and systemic B cell and Th1 responses induced following ocularmucosal delivery ofmultiple epitopes of herpes simplex virus type 1 glycoprotein D together with cytosine-phosphate-guanine adjuvant. Vaccine 23:873–883

    PubMed  CAS  Google Scholar 

  99. Hogarth PJ, Jahans KJ, Hecker R, Hewinson RG, Chambers MA (2003) Evaluation of adjuvants for protein vaccines against tuberculosis in guinea pigs. Vaccine 21:977–982

    PubMed  CAS  Google Scholar 

  100. Vleugels B, Ververken C, Goddeeris BM (2002) Stimulatory effect of CpG sequences on humoral response in chickens. Poult Sci 81:1317–1321

    PubMed  CAS  Google Scholar 

  101. Alcon VL, Foldvari M, Snider M, Willson P, Gomis S, Hecker R, Babiuk LA, Baca-Estrada ME (2003) Induction of protective immunity in pigs after immunisation with CpG oligodeoxynucleotides formulated in a lipid-based delivery system (Biphasix). Vaccine 21:1811–1814

    PubMed  CAS  Google Scholar 

  102. Kringel H, Dubey JP, Beshah E, Hecker R, Urban JF Jr (2004) CpG-oligodeoxynucleotides enhance porcine immunity to Toxoplasma gondii. Vet Parasitol 123:55–66

    PubMed  CAS  Google Scholar 

  103. Rankin R, Pontarollo R, Gomis S, Karvonen B, Willson P, Loehr BI, Godson DL, Babiuk LA, Hecker R, van Drunen Littel-van den Hurk S (2002) CpG-containing oligodeoxynucleotides augment and switch the immune responses of cattle to bovine herpesvirus-1 glycoprotein D. Vaccine 20:3014–3022

    PubMed  CAS  Google Scholar 

  104. Wedlock DN, Denis M, Skinner MA, Koach J, de Lisle GW, Vordermeier HM, Hewinson RG, van Drunen Littel-van den Hurk S, Babiuk LA, Hecker R, Buddle BM (2005) Vaccination of cattle with Mycobacterium bovis culture filtrate proteins and CpG oligodeoxynucleotides induces protection against bovine tuberculosis. Vet Immunol Immunopathol 106:53–63

    PubMed  CAS  Google Scholar 

  105. Ioannou XP, Gomis SM, Karvonen B, Hecker R, Babiuk LA, van Drunen Littel-van den Hurk S (2002) CpG-containing oligodeoxynucleotides, in combination with conventional adjuvants, enhance the magnitude and change the bias of the immune responses to a herpesvirus glycoprotein. Vaccine 21:127–137

    PubMed  CAS  Google Scholar 

  106. Rafati S, Nakhaee A, Taheri T, Taslimi Y, Darabi H, Eravani D, Sanos S, Kaye P, Taghikhani M, Jamshidi S, Rad MA (2005) Protective vaccination against experimental canine visceral leishmaniasis using a combination of DNA and protein immunization with cysteine proteinases type I and II of L. infantum. Vaccine 23:3716–3725

    PubMed  CAS  Google Scholar 

  107. Davis HL, Suparto II, Weeratna RR, Jumintarto, Iskandriati DD, Chamzah SS, Ma’ruf AA, Nente CC, Pawitri DD, Krieg AM, Heriyanto, Smits W, Sajuthi DD (2000) CpG DNA overcomes hyporesponsiveness to hepatitis B vaccine in orangutans. Vaccine 18:1920–1924

    PubMed  CAS  Google Scholar 

  108. Kumar S, Jones TR, Oakley MS, Zheng H, Kuppusamy SP, Taye A, Krieg AM, Stowers AW, Kaslow DC, Hoffman SL (2004) CpGoligodeoxynucleotide andmontanide ISA 51 adjuvant combination enhanced the protective efficacy of a subunitmalaria vaccine. Infect Immun 72:949–957

    PubMed  CAS  Google Scholar 

  109. Cooper CL, Davis HL, Angel JB, Morris ML, Elfer SM, Seguin I, Krieg AM, Cameron DW (2005) CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 19:1473–1479

    PubMed  CAS  Google Scholar 

  110. Cooper CL, Davis HL, Morris ML, Efler SM, Adhami MA, Krieg AM, Cameron DW, Heathcote J (2004) CpG7909, animmunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study. J Clin Immunol 24:693–702

    PubMed  CAS  Google Scholar 

  111. Cooper CL, Davis HL, Morris ML, et al (2004) Safety and immunogenicity of CpG 7909 injection as an adjuvant to Fluarix influenza vaccine. Vaccine 22:3136–3143

    PubMed  CAS  Google Scholar 

  112. Halperin SA, Van Nest G, Smith B, Abtahi S, Whiley H, Eiden JJ (2003) A phase I study of the safety andimmunogenicity of recombinanthepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Vaccine 21:2461–2467

    PubMed  CAS  Google Scholar 

  113. Speiser DE, Lienard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F, Krieg AM, Cerottini JC, Romero P (2005) Rapid and strong human CD8(+)Tcell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 115:739–746

    PubMed  CAS  Google Scholar 

  114. Weeratna RD, McCluskie MJ, Xu Y, Davis HL (2000) CpG DNA induces stronger immune responses with less toxicity than other adjuvants. Vaccine 18:1755–1762

    PubMed  CAS  Google Scholar 

  115. Sugai T, Mori M, Nakazawa M, Ichino M, Naruto T, Kobayashi N, Kobayashi Y, Minami M, Yokota S (2005) ACpG-containing oligodeoxynucleotide as anefficient adjuvant counterbalancing the Th1/Th2 immune response in diphtheria-tetanuspertussis vaccine. Vaccine 23:5450–5456

    PubMed  CAS  Google Scholar 

  116. Oumouna M, Mapletoft JW, Karvonen BC, Babiuk LA, van Drunen Littel-van den Hurk S (2005) Formulation with CpG oligodeoxynucleotides prevents induction of pulmonary immunopathology following priming with formalin-inactivated or commercial killed bovine respiratory syncytial virus vaccine. JVirol 79:2024–2032

    CAS  Google Scholar 

  117. Hancock GE, Heers KM, Pryharski KS, Smith JD, Tiberio L (2003) Adjuvants recognized by toll-like receptors inhibit the induction of polarized type 2 T cell responsesbynatural attachment (G)proteinof respiratory syncytial virus. Vaccine 21:4348–4358

    PubMed  CAS  Google Scholar 

  118. Brazolot Millan CL, Weeratna R, Krieg AM, Siegrist CA, Davis HL (1998) CpG DNA can induce strong Th1 humoral and cell-mediated immune responses against hepatitis B surface antigen in young mice. Proc Natl Acad Sci USA 95:15553–15558

    PubMed  CAS  Google Scholar 

  119. Weeratna RD, Brazolot Millan CL, McCluskie MJ, Siegrist CA, Davis HL (2001) Priming of immune responses to hepatitis B surface antigen in young mice immunized in the presence of maternally derived antibodies. FEMS Immunol Med Microbiol 30:241–247

    PubMed  CAS  Google Scholar 

  120. Schirmbeck R, Reimann J (2001) Modulation of gene-gun-mediated Th2 immunity to hepatitis B surface antigen by bacterial CpGmotifs or IL-12. Intervirology 44:115–123

    PubMed  CAS  Google Scholar 

  121. Zhou X, Zheng L, Liu L, Xiang L, Yuan Z (2003) T helper 2 immunity to hepatitis B surface antigen primed by gene-gun-mediated DNA vaccination can be shifted towards T helper 1 immunity by codelivery of CpGmotif-containing oligodeoxynucleotides. Scand J Immunol 58:350–357

    PubMed  CAS  Google Scholar 

  122. Weeratna RD, Brazolot Millan CL, McCluskie MJ, Davis HL (2001) CpG ODN can re-direct the Th bias of established Th2 immune responses in adult and young mice. FEMS Immunol Med Microbiol 32:65–71

    PubMed  CAS  Google Scholar 

  123. Manning BM, Enioutina EY, Visic DM, Knudson AD, Daynes RA (2001) CpGDNA functions as an effective adjuvant for the induction of immune responses in aged mice. Exp Gerontol 37:107–126

    PubMed  CAS  Google Scholar 

  124. Maletto B, Ropolo A, Moron V, Pistoresi-Palencia MC (2002) CpG-DNAstimulates cellular and humoral immunity and promotes Th1 differentiation in aged BALB/c mice. J Leukoc Biol 72:447–454

    PubMed  CAS  Google Scholar 

  125. Alignani D, Maletto B, Liscovsky M, Ropolo A, Moron G, Pistoresi-Palencia MC (2005) Orally administered OVA/CpG-ODN induces specificmucosal and systemic immune response in young and aged mice. J Leukoc Biol 77:898–905

    PubMed  CAS  Google Scholar 

  126. Weeratna R, Comanita L, Davis HL (2003) CPG ODN allows lower dose of antigen against hepatitis B surface antigen in BALB/c mice. Immunol Cell Biol 81:59–62

    PubMed  CAS  Google Scholar 

  127. Siegrist CA, Pihlgren M, Tougne C, Efler SM, Morris ML, AlAdhami MJ, Cameron DW, Cooper CL, Heathcote J, Davis HL, Lambert PH (2004) Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. Vaccine 23:615–622

    PubMed  CAS  Google Scholar 

  128. McGhee JR, Mestecky J, Dertzbaugh MT, Eldridge JH, Hirasawa M, Kiyono H (1992) The mucosal immune system: from fundamental concepts to vaccine development. Vaccine 10:75–88

    PubMed  CAS  Google Scholar 

  129. Moldoveanu Z, Love-Homan L, Huang WQ, Krieg AM (1998) CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 16:1216–1224

    PubMed  CAS  Google Scholar 

  130. Gallichan WS, Woolstencroft RN, Guarasci T, McCluskie MJ, Davis HL, Rosenthal KL (2001) Intranasal immunization with CpG oligodeoxynucleotides as an adjuvant dramatically increases IgA and protectionag ainst herpes simplex virus-2 in the genital tract. J Immunol 166:3451–3457

    PubMed  CAS  Google Scholar 

  131. McCluskie MJ, Davis HL (1998) CpG DNA is a potent enhancer of systemic and mucosal immune responses against hepatitis B surface antigen with intranasal administration to mice. J Immunol 161:4463–4466

    PubMed  CAS  Google Scholar 

  132. McCluskie MJ, Davis HL (2001) Oral, intrarectal and intranasal immunizations using CpG and non-CpG oligodeoxynucleotides as adjuvants. Vaccine 19:413–422

    Google Scholar 

  133. Kwant A, Rosenthal KL (2004) Intravaginal immunization with viral subunit protein plus CpG oligodeoxynucleotides induces protective immunity against HSV-2. Vaccine 22:3098–3104

    PubMed  CAS  Google Scholar 

  134. McCluskie MJ, Weeratna RD, Krieg AM, Davis HL (2001) CpG DNA is an effective oral adjuvant to protein antigens in mice. Vaccine 19:950–957

    Google Scholar 

  135. Dong JL, Liang BG, Jin YS, Zhang WJ, Wang T (2005) Oral immunization with pBsVP6-transgenic alfalfa protects mice against rotavirus infection. Virology 339:153–163

    PubMed  CAS  Google Scholar 

  136. Dumais N, Patrick A, Moss RB, Davis HL, Rosenthal KL (2002) Mucosal immunization with inactivated human immunodeficiency virus plus CpG oligodeoxynucleotides induces genital immuneresponses andprotectionagainst intravaginal challenge. J Infect Dis 186:1098–1105

    PubMed  CAS  Google Scholar 

  137. Berry LJ, Hickey DK, Skelding KA, Bao S, Rendina AM, Hansbro PM, Gockel CM, Beagley KW (2004) Transcutaneous immunization with combined cholera toxin and CpG adjuvant protects against Chlamydiamuridarum genital tract infection. Infect Immun 72:1019–1028

    PubMed  CAS  Google Scholar 

  138. Joseph A, Louria-Hayon I, Plis-Finarov A, Zeira E, Zakay-Rones Z, Raz E, Hayashi T, Takabayashi K, Barenholz Y, Kedar E (2002) Liposomal immunostimulatory DNA sequence (ISS-ODN): an efficient parenteral and mucosal adjuvant for influenza and hepatitis B vaccines. Vaccine 20:3342–3354

    PubMed  CAS  Google Scholar 

  139. McCluskie MJ, Weeratna RD, Davis HL (2000) Intranasal immunization of mice with CpG DNA induces strong systemic andmucosal responses that are influenced by other mucosal adjuvants and antigen distribution. Mol Med 6:867–877

    PubMed  CAS  Google Scholar 

  140. Jiang W, Baker HJ, Smith BF (2003) Mucosal immunization with helicobacter, CpG DNA, and cholera toxin is protective. Infect Immun 71:40–46

    PubMed  CAS  Google Scholar 

  141. McCluskie MJ, Weeratna RD, Clements JD, Davis HL (2001) Mucosal immunization of mice using CpG DNA and/or mutants of the heat-labile enterotoxin of Escherichia coli as adjuvants. Vaccine 19:3759–3768

    PubMed  CAS  Google Scholar 

  142. Olszewska W, Partidos CD, Steward MW (2000) Antipeptide antibody responses following intranasal immunization: effectiveness of mucosal adjuvants. Infect Immun 68:4923–4929

    PubMed  CAS  Google Scholar 

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  1. Coley Pharmaceutical Group, Inc., 93 Worcester Street, Suite 101, Wellesley, MA, 02481, USA

    M. J. McCluskie & A. M. Krieg

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McCluskie, M.J., Krieg, A.M. (2006). Enhancement of Infectious Disease Vaccines Through TLR9-Dependent Recognition of CpG DNA. In: Pulendran, B., Ahmed, R. (eds) From Innate Immunity to Immunological Memory. Current Topics in Microbiology and Immunology, vol 311. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-32636-7_6

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