Skip to main content
SpringerLink
Log in

CpG Oligonucleotides as Vaccine Adjuvants

  • Protocol
  • First Online:
Book cover DNA Vaccines

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2197))

Abstract

CpG Oligonucleotides (ODN) are immunomodulatory synthetic oligonucleotides specifically designed to stimulate Toll-like receptor 9. TLR9 is expressed on human plasmacytoid dendritic cells and B cells and triggers an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. This chapter reviews recent progress in understanding the mechanism of action of CpG ODN and provides an overview of human clinical trial results using CpG ODN to improve vaccines for the prevention/treatment of cancer, allergy, and infectious disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Julier Z, Park AJ, Briquez PS et al (2017) Promoting tissue regeneration by modulating the immune system. Acta Biomater 53:13–28

    Article  CAS  PubMed  Google Scholar 

  2. Klein U, la-Favera R (2008) Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 8:22–33

    Article  CAS  PubMed  Google Scholar 

  3. Wienands J, Engels N (2016) Control of memory B cell responses by extrinsic and intrinsic mechanisms. Immunol Lett 178:27–30

    Article  CAS  PubMed  Google Scholar 

  4. Engels N, Wienands J (2018) Memory control by the B cell antigen receptor. Immunol Rev 283:150–160

    Article  CAS  PubMed  Google Scholar 

  5. Schmidlin H, Diehl SA, Blom B (2009) New insights into the regulation of human B-cell differentiation. Trends Immunol 30:277–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sarkander J, Hojyo S, Tokoyoda K (2016) Vaccination to gain humoral immune memory. Clin Transl Immunology 5:e120

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cockburn IA, Chen YC, Overstreet MG et al (2010) Prolonged antigen presentation is required for optimal CD8+ T cell responses against malaria liver stage parasites. PLoS Pathog 6:e1000877

    Article  PubMed  PubMed Central  Google Scholar 

  8. Vezys V, Yates A, Casey KA et al (2009) Memory CD8 T-cell compartment grows in size with immunological experience. Nature 457:196–199

    Article  CAS  PubMed  Google Scholar 

  9. Shah RR, Hassett KJ, Brito LA (2017) Overview of vaccine adjuvants: introduction, history, and current status. Methods Mol Biol 1494:1–13

    Article  CAS  PubMed  Google Scholar 

  10. Dresser DW (1961) Effectiveness of lipid and lipidophilic substances as adjuvants. Nature 191:1169–1171

    Article  CAS  PubMed  Google Scholar 

  11. Sarkar I, Garg R, van den Hurk v DL (2019) Selection of adjuvants for vaccines targeting specific pathogens. Expert Rev Vaccines 18:505–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lemaitre B, Nicolas E, Michaut L et al (1996) The dorsoventral regulatory gene cassette spatzle/toll/cactus controls the potent antifungal response in drosophila adults. Cell 86:973–983

    Article  CAS  PubMed  Google Scholar 

  13. Poltorak A, He X, Smirnova I et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088

    Article  CAS  PubMed  Google Scholar 

  14. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216

    Article  CAS  PubMed  Google Scholar 

  15. Xiao H, Peng Y, Hong Y et al (2013) Local administration of TLR ligands rescues the function of tumor-infiltrating CD8 T cells and enhances the antitumor effect of lentivector immunization. J Immunol 190:5866–5873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hemmi H, Takeuchi O, Kawai T et al (2000) A toll-like receptor recognizes bacterial DNA. Nature 408:740–745

    Article  CAS  PubMed  Google Scholar 

  17. O'Neill LA, Golenbock D, Bowie AG (2013) The history of toll-like receptors - redefining innate immunity. Nat Rev Immunol 13:453–460

    Article  CAS  PubMed  Google Scholar 

  18. Hornung V, Rothenfusser S, Britsch S et al (2002) Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168:4531–4537

    Article  CAS  PubMed  Google Scholar 

  19. Kanzler H, Barrat FJ, Hessel EM et al (2007) Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists. Nat Med 13:552–559

    Article  CAS  PubMed  Google Scholar 

  20. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511

    Article  CAS  PubMed  Google Scholar 

  21. Lorne E, Dupont H, Abraham E (2010) Toll-like receptors 2 and 4: initiators of non-septic inflammation in critical care medicine? Intensive Care Med 36:1826–1835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Redecke V, Hacker H, Datta SK et al (2004) Cutting edge: activation of toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 172:2739–2743

    Article  CAS  PubMed  Google Scholar 

  23. Dabbagh K, Dahl ME, Stepick-Biek P et al (2002) Toll-like receptor 4 is required for optimal development of Th2 immune responses: role of dendritic cells. J Immunol 168:4524–4530

    Article  CAS  PubMed  Google Scholar 

  24. Farrokhi S, Abbasirad N, Movahed A et al (2017) TLR9-based immunotherapy for the treatment of allergic diseases. Immunotherapy 9:339–346

    Article  CAS  PubMed  Google Scholar 

  25. Shirota H, Sano K, Kikuchi T et al (2000) Regulation of T-helper type 2 cell and airway eosinophilia by transmucosal coadministration of antigen and oligodeoxynucleotides containing CpG motifs. Am J Respir Cell Mol Biol 22:176–182

    Article  CAS  PubMed  Google Scholar 

  26. Shirota H, Sano K, Kikuchi T et al (2000) Regulation of murine airway eosinophilia and Th2 cells by antigen-conjugated CpG oligodeoxynucleotides as a novel antigen-specific immunomodulator. J Immunol 164:5575–5582

    Article  CAS  PubMed  Google Scholar 

  27. Kim YH, Girardi M, Duvic M et al (2010) Phase I trial of a toll-like receptor 9 agonist, PF-3512676 (CPG 7909), in patients with treatment-refractory, cutaneous T-cell lymphoma. J Am Acad Dermatol 63:975–983

    Article  CAS  PubMed  Google Scholar 

  28. Latz E, Schoenemeyer A, Visintin A et al (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 5:190–198

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki Y, Wakita D, Chamoto K et al (2004) Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity. Cancer Res 64:8754–8760

    Article  CAS  PubMed  Google Scholar 

  30. Kadowaki N, Ho S, Antonenko S et al (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194:863–869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bernasconi NL, Onai N, Lanzavecchia A (2003) A role for toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101:4500–4504

    Article  CAS  PubMed  Google Scholar 

  32. Ewald SE, Lee BL, Lau L et al (2008) The ectodomain of toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456:658–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Park B, Brinkmann MM, Spooner E et al (2008) Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol 9:1407–1414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ewald SE, Engel A, Lee J et al (2011) Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J Exp Med 208:643–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sepulveda FE, Maschalidi S, Colisson R et al (2009) Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. Immunity 31:737–748

    Article  CAS  PubMed  Google Scholar 

  36. Kumagai Y, Takeuchi O, Akira S (2008) TLR9 as a key receptor for the recognition of DNA. Adv Drug Deliv Rev 60:795–804

    Article  CAS  PubMed  Google Scholar 

  37. Klaschik S, Tross D, Klinman DM (2009) Inductive and suppressive networks regulate TLR9-dependent gene expression in vivo. J Leukoc Biol 85:788–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Saitoh S, Miyake K (2009) Regulatory molecules required for nucleotide-sensing toll-like receptors. Immunol Rev 227:32–43

    Article  CAS  PubMed  Google Scholar 

  39. Klaschik S, Tross D, Shirota H et al (2010) Short- and long-term changes in gene expression mediated by the activation of TLR9. Mol Immunol 47:1317–1324

    Article  CAS  PubMed  Google Scholar 

  40. Mutwiri GK, Nichani AK, Babiuk S et al (2004) Strategies for enhancing the immunostimulatory effects of CpG oligodeoxynucleotides. J Control Release 97:1–17

    Article  CAS  PubMed  Google Scholar 

  41. Verthelyi D, Ishii KJ, Gursel M et al (2001) Human peripheral blood cells differentially recognize and respond to two distinct CPG motifs. J Immunol 166:2372–2377

    Article  CAS  PubMed  Google Scholar 

  42. Hartmann G, Battiany J, Poeck H et al (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

    Article  CAS  PubMed  Google Scholar 

  43. Krug A, Towarowski A, Britsch S et al (2001) Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol 31:3026–3037

    Article  CAS  PubMed  Google Scholar 

  44. Guiducci C, Ott G, Chan JH et al (2006) Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J Exp Med 203:1999–2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Honda K, Ohba Y, Yanai H et al (2005) Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035–1040

    Article  CAS  PubMed  Google Scholar 

  46. Storni T, Ruedl C, Schwarz K et al (2004) Nonmethylated CG motifs packaged into virus-like particles induce protective cytotoxic T cell responses in the absence of systemic side effects. J Immunol 172:1777–1785

    Article  CAS  PubMed  Google Scholar 

  47. Goldinger SM, Dummer R, Baumgaertner P et al (2012) Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8(+) T-cell responses in melanoma patients. Eur J Immunol 42:3049–3061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Speiser DE, Schwarz K, Baumgaertner P et al (2010) Memory and effector CD8 T-cell responses after nanoparticle vaccination of melanoma patients. J Immunother 33:848–858

    Article  CAS  PubMed  Google Scholar 

  49. Marshall JD, Fearon K, Abbate C et al (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

    Article  CAS  PubMed  Google Scholar 

  50. Vollmer J, Weeratna R, Payette P et al (2004) Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur J Immunol 34:251–262

    Article  CAS  PubMed  Google Scholar 

  51. Vollmer J, Krieg AM (2009) Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Adv Drug Deliv Rev 61:195–204

    Article  CAS  PubMed  Google Scholar 

  52. Samulowitz U, Weber M, Weeratna R et al (2010) A novel class of immune-stimulatory CpG oligodeoxynucleotides unifies high potency in type I interferon induction with preferred structural properties. Oligonucleotides 20:93–101

    Article  CAS  PubMed  Google Scholar 

  53. Davis HL, Weeranta R, Waldschmidt TJ et al (1998) CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J Immunol 160:870–876

    Article  CAS  PubMed  Google Scholar 

  54. Kobayashi H, Horner AA, Takabayashi K et al (1999) Immunostimulatory DNA pre-priming: a novel approach for prolonged Th1-biased immunity. Cell Immunol 198:69–75

    Article  CAS  PubMed  Google Scholar 

  55. Krieg AM, Yi A, Matson S et al (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–548

    Article  CAS  PubMed  Google Scholar 

  56. Hartmann G, Weeratna RD, Ballas ZK et al (2000) Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 164:1617–1624

    Article  CAS  PubMed  Google Scholar 

  57. Ruprecht CR, Lanzavecchia A (2006) Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur J Immunol 36:810–816

    Article  CAS  PubMed  Google Scholar 

  58. Huggins J, Pellegrin T, Felgar RE et al (2007) CpG DNA activation and plasma-cell differentiation of. Blood 109:1611–1619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jiang W, Lederman MM, Harding CV et al (2007) TLR9 stimulation drives naive B cells to proliferate and to attain enhanced antigen presenting function. Eur J Immunol 37:2205–2213

    Article  CAS  PubMed  Google Scholar 

  60. Eckl-Dorna J, Batista FD (2009) BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation. Blood 113:3969–3977

    Article  CAS  PubMed  Google Scholar 

  61. Wang Z, Karras JG, Colarusso TP et al (1997) Unmethylated CpG motifs protect murine B lymphocytes against Fas-mediated apoptosis. Cell Immunol 180:162–167

    Article  CAS  PubMed  Google Scholar 

  62. Kerkmann M, Rothenfusser S, Hornung V et al (2003) Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J Immunol 170:4465–4474

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  64. Jakob T, Walker PS, Krieg AM et al (1998) Activation of cutaneous dendritic cells by CpG containing oligodeoxynucleotides: a role for dendritic cells in the augmentation of Th1 responses by immunostimulatory DNA. J Immunol 161:3042–3049

    Article  CAS  PubMed  Google Scholar 

  65. Sparwasser T, Koch E, Vabulas RM et al (1998) Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 28:2045–2054

    Article  CAS  PubMed  Google Scholar 

  66. Ban E, Dupre L, Hermann E et al (2000) CpG motifs induce Langerhans cell migration in vivo. Int Immunol 12:737–745

    Article  CAS  PubMed  Google Scholar 

  67. Behboudi S, Chao D, Klenerman P et al (2000) The effects of DNA containing CpG motif on dendritic cells. Immunology 99:361–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hartmann G, Krieg AM (1999) CpG DNA and LPS induce distinct patterns of activation in human monocytes. Gene Ther 6:893–903

    Article  CAS  PubMed  Google Scholar 

  69. Pichyangkul S, Yongvanitchit K, Kum-arb U et al (2001) Whole blood cultures to assess the immunostimulatory activities of CpG oligodeoxynucleotides. J Immunol Methods 247:83–94

    Article  CAS  PubMed  Google Scholar 

  70. Stacey KJ, Sweet MJ, Hume DA (1996) Macrophages ingest and are activated by bacterial DNA. J Immunol 157:2116–2120

    Article  CAS  PubMed  Google Scholar 

  71. Sato T, Shimosato T, Ueda A et al (2015) Intrapulmonary delivery of CpG microparticles eliminates lung tumors. Mol Cancer Ther 14:2198–2205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sun S, Zhang X, Tough DF, Sprent J (1998) Type I interferon-mediated stimulation of T cells by CpG DNA. J Exp Med 188:2335–2342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bendigs S, Salzer U, Lipford GB et al (1999) CpG-oligodeoxynucleotides co-stimulate primary T cells in the absence of antigen-presenting cells. Eur J Immunol 29:1209–1218

    Article  CAS  PubMed  Google Scholar 

  74. Kranzer K, Bauer M, Lipford GB et al (2000) CpG-oligodeoxynucleotides enhance T-cell receptor-triggered interferon-gamma production and up-regulation of CD69 via induction of antigen-presenting cell-derived interferon type I and interleukin-12. Immunology 99:170–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sparwasser T, Vabulas RM, Villmow B et al (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

    Article  CAS  PubMed  Google Scholar 

  76. Vabulas RM, Pircher H, Lipford GB et al (2000) CpG-DNA activates in vivo T cell epitope presenting dendritic cells to trigger protective anti-viral cytotoxic T cell responses. J Immunol 164:2372–2378

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sun S, Zhang X, Tough D et al (2000) Multiple effects of immunostimulatory DNA on T cells and the role of type I interferons. Springer Semin Immunopathol 22:77–84

    Article  CAS  PubMed  Google Scholar 

  79. Tascon RE, Ragno S, Lowrie DB et al (2000) Immunostimulatory bacterial DNA sequences activate dendritic cells and promote priming and differentiation of CD8+ T cells. Immunology 99:1–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lipford GB, Bauer M, Blank C et al (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

    Article  CAS  PubMed  Google Scholar 

  81. Yang WC, Sun HW, Sun HQ et al (2018) Intranasal immunization with immunodominant epitope peptides derived from HpaA conjugated with CpG adjuvant protected mice against helicobacter pylori infection. Vaccine 36:6301–6306

    Article  CAS  PubMed  Google Scholar 

  82. Hayashi T, Momota M, Kuroda E et al (2018) DAMP-inducing adjuvant and PAMP adjuvants parallelly enhance protective Type-2 anD-type-1 immune responses to influenza split vaccination. Front Immunol 9:2619

    Article  PubMed  PubMed Central  Google Scholar 

  83. Yu P, Yan J, Wu W et al (2018) A CpG oligodeoxynucleotide enhances the immune response to rabies vaccination in mice. Virol J 15:174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hensel MT, Marshall JD, Dorwart MR et al (2017) Prophylactic herpes simplex virus 2 (HSV-2) vaccines Adjuvanted with stable emulsion and toll-like receptor 9 agonist induce a robust HSV-2-specific cell-mediated immune response, protect against symptomatic disease, and reduce the latent viral reservoir. J Virol 91:e02257-16

    Article  PubMed  PubMed Central  Google Scholar 

  85. Reeman S, Gates AJ, Pulford DJ et al (2017) Protection of mice from lethal vaccinia virus infection by vaccinia virus protein subunits with a CpG adjuvant. Viruses 9:378

    Article  PubMed Central  Google Scholar 

  86. Da Silva DM, Skeate JG, Chavez-Juan E et al (2019) Therapeutic efficacy of a human papillomavirus type 16 E7 bacterial exotoxin fusion protein adjuvanted with CpG or GPI-0100 in a preclinical mouse model for HPV-associated disease. Vaccine 37:2915–2924

    Article  PubMed  Google Scholar 

  87. Yang Y, Che Y, Zhao Y et al (2019) Prevention and treatment of cervical cancer by a single administration of human papillomavirus peptide vaccine with CpG oligodeoxynucleotides as an adjuvant in vivo. Int Immunopharmacol 69:279–288

    Article  CAS  PubMed  Google Scholar 

  88. 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

    Article  CAS  PubMed  Google Scholar 

  89. von HC, Mariotti S, Teloni R et al (2001) The adjuvant effect of synthetic oligodeoxynucleotide containing CpG motif converts the anti-Haemophilus influenzae type b glycoconjugates into efficient anti-polysaccharide and anti-carrier polyvalent vaccines. Vaccine 19:3058–3066

    Article  Google Scholar 

  90. Kovarik J, Bozzotti P, Love-Homan L et al (1999) CpG oligodeoxynucleotides can circumvent the Th2 polarization of neonatal responses to vaccines but may fail to fully redirect Th2 responses established by neonatal priming. J Immunol 162:1611–1617

    Article  CAS  PubMed  Google Scholar 

  91. Eastcott JW, Holmberg CJ, Dewhirst FE et al (2001) Oligonucleotide containing CpG motifs enhances immune response to mucosally or systemically administered tetanus toxoid. Vaccine 19:1636–1642

    Article  CAS  PubMed  Google Scholar 

  92. Al-Mariri A, Tibor A, Mertens P et al (2001) Protection of BALB/c mice against Brucella abortus 544 challenge by vaccination with bacterioferritin or P39 recombinant proteins with CpG oligodeoxynucleotides as adjuvant. Infect Immun 69:4816–4822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. xie H, Gursel I, Ivins BE et al (2005) CpG oligodeoxynucleotides adsorbed onto polylactide-co-glycolide microparticles improve the immunogenicity and protective activity of the licensed anthrax vaccine. Infect Immun 73:828–833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Fogg CN, Americo JL, Lustig S et al (2007) Adjuvant-enhanced antibody responses to recombinant proteins correlates with protection of mice and monkeys to orthopoxvirus challenges. Vaccine 25:2787–2799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mendez S, Tabbara K, Belkaid Y et al (2003) Coinjection with CpG-containing immunostimulatory oligodeoxynucleotides reduces the pathogenicity of a live vaccine against cutaneous Leishmaniasis but maintains its potency and durability. Infect Immun 71:5121–5129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Klinman DM, Currie D, Lee G et al (2007) Systemic but not mucosal immunity induced by AVA prevents inhalational anthrax. Microbes Infect 9:1478–1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Klinman DM, xie H, Little SF et al (2004) CpG oligonucleotides improve the protective immune response induced by the anthrax vaccination of rhesus macaques. Vaccine 22:2881–2886

    Article  CAS  PubMed  Google Scholar 

  98. Tengvall S, Lundqvist A, Eisenberg RJ et al (2006) Mucosal administration of CpG oligodeoxynucleotide elicits strong CC and CXC chemokine responses in the vagina and serves as a potent Th1-tilting adjuvant for recombinant gD2 protein vaccination against genital herpes. J Virol 80:5283–5291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gallichan WS, Woolstencroft RN, Guarasci T et al (2001) Intranasal immunization with CpG oligodeoxynucleotides as an adjuvant dramatically increases IgA and protection against herpes simplex virus-2 in the genital tract. J Immunol 166:3451–3457

    Article  CAS  PubMed  Google Scholar 

  100. Lin YL, Chow YH, Huang LM et al (2018) A CpG-adjuvanted intranasal enterovirus 71 vaccine elicits mucosal and systemic immune responses and protects human SCARB2-transgenic mice against lethal challenge. Sci Rep 8:10713

    Article  PubMed  PubMed Central  Google Scholar 

  101. Nesburn AB, Ramos TV, Zhu X et al (2005) Local and systemic B cell and Th1 responses induced following ocular mucosal delivery of multiple epitopes of herpes simplex virus type 1 glycoprotein D together with cytosine-phosphate-guanine adjuvant. Vaccine 23:873–883

    Article  CAS  PubMed  Google Scholar 

  102. Huang CF, Wang CC, Wu TC et al (2008) Neonatal sublingual vaccination with salmonella proteins and adjuvant cholera toxin or CpG oligodeoxynucleotides induces mucosal and systemic immunity in mice. J Pediatr Gastroenterol Nutr 46:262–271

    Article  CAS  PubMed  Google Scholar 

  103. McCluskie MJ, Weeratna RD, Krieg AM et al (2000) CpG DNA is an effective oral adjuvant to protein antigens in mice. Vaccine 19:950–957

    Article  CAS  PubMed  Google Scholar 

  104. Kayraklioglu N, Scheiermann J, Alvord WG et al (2017) Effect of calcium carbonate encapsulation on the activity of orally administered CpG oligonucleotides. Mol Ther Nucleic Acids 8:243–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Miller RA (1989) The cell biology of aging: immunologic models. J Gerontol 44:B4

    Article  CAS  PubMed  Google Scholar 

  106. Thoman ML, Weigle WO (1989) The cellular and subcellular bases of Immunosenescence. Adv Immunol 46:221–261

    Article  CAS  PubMed  Google Scholar 

  107. Qin W, Jiang J, Chen Q et al (2004) CpG ODN enhances immunization effects of hepatitis B vaccine in aged mice. Cell Mol Immunol 1:148–152

    CAS  PubMed  Google Scholar 

  108. Siegrist CA, Pihlgren M, Tougne C et al (2004) Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. Vaccine 23:615–622

    Article  CAS  PubMed  Google Scholar 

  109. Sen G, Chen Q, Snapper CM (2006) Immunization of aged mice with a pneumococcal conjugate vaccine combined with an unmethylated CpG-containing oligodeoxynucleotide restores defective immunoglobulin G antipolysaccharide responses and specific CD4+-T-cell priming to young adult levels. Infect Immun 74:2177–2186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Fukuyama Y, Ikeda Y, Ohori J et al (2015) A molecular mucosal adjuvant to enhance immunity against pneumococcal infection in the elderly. Immune Netw 15:9–15

    Article  PubMed  PubMed Central  Google Scholar 

  111. Brazolot Millan CL, Weeratna R, Krieg AM et al (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 U S A 95:15553–15558

    Article  CAS  PubMed  Google Scholar 

  112. van Haren SD, Ganapathi L, Bergelson I et al (2016) In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant. Cytokine 83:99–109

    Article  PubMed  PubMed Central  Google Scholar 

  113. Savransky V, Shearer JD, Gainey MR et al (2017) Correlation between anthrax lethal toxin neutralizing antibody levels and survival in Guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate. Vaccine 35:4952–4959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mapletoft JW, Oumouna M, Townsend HG et al (2006) Formulation with CpG oligodeoxynucleotides increases cellular immunity and protection induced by vaccination of calves with formalin-inactivated bovine respiratory syncytial virus. Virology 353:316–323

    Article  CAS  PubMed  Google Scholar 

  115. Muangthai K, Tankaew P, Varinrak T et al (2018) Intranasal immunization with a recombinant outer membrane protein H based Haemorrhagic septicemia vaccine in dairy calves. J Vet Med Sci 80:68–76

    Article  CAS  PubMed  Google Scholar 

  116. Linghua Z, Xingshan T, Fengzhen Z (2008) In vivo oral administration effects of various oligodeoxynucleotides containing synthetic immunostimulatory motifs in the immune response to pseudorabies attenuated virus vaccine in newborn piglets. Vaccine 26:224–233

    Article  PubMed  Google Scholar 

  117. Linghua Z, Xingshan T, Fengzhen Z (2007) Vaccination with Newcastle disease vaccine and CpG oligodeoxynucleotides induces specific immunity and protection against Newcastle disease virus in SPF chicken. Vet Immunol Immunopathol 115:216–222

    Article  PubMed  Google Scholar 

  118. Singh SM, Alkie TN, Hodgins DC et al (2015) Systemic immune responses to an inactivated, whole H9N2 avian influenza virus vaccine using class B CpG oligonucleotides in chickens. Vaccine 33:3947–3952

    Article  CAS  PubMed  Google Scholar 

  119. Yuan F, Chu Y, Qi L et al (2017) Immunoprotection induced by CpG-ODN/poly(I:C) combined with recombinant gp90 protein in chickens against reticuloendotheliosis virus infection. Antivir Res 147:1–10

    Article  CAS  PubMed  Google Scholar 

  120. Lopez AM, Hecker R, Mutwiri G et al (2006) Formulation with CpG ODN enhances antibody responses to an equine influenza virus vaccine. Vet Immunol Immunopathol 114:103–110

    Article  CAS  PubMed  Google Scholar 

  121. Klier J, Lehmann B, Fuchs S et al (2015) Nanoparticulate CpG immunotherapy in RAO-affected horses: phase I and IIa study. J Vet Intern Med 29:286–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Klier J, Fuchs S, May A et al (2012) A nebulized gelatin nanoparticle-based CpG formulation is effective in immunotherapy of allergic horses. Pharm Res 29:1650–1657

    Article  CAS  PubMed  Google Scholar 

  123. Ren J, Sun L, Yang L et al (2010) A novel canine favored CpG oligodeoxynucleotide capable of enhancing the efficacy of an inactivated aluminum-adjuvanted rabies vaccine of dog use. Vaccine 28:2458–2464

    Article  CAS  PubMed  Google Scholar 

  124. Verthelyi D, Kenney RT, Seder RA et al (2002) CpG oligodeoxynucleotides as vaccine adjuvants in primates. J Immunol 168:1659–1663

    Article  CAS  PubMed  Google Scholar 

  125. Davis HL, Suparto II, Weeratna RR et al (2000) CpG DNA overcomes hyporesponsiveness to hepatitis B vaccine in orangutans. Vaccine 18:1920–1924

    Article  CAS  PubMed  Google Scholar 

  126. Jones TR, Obaldia N III, Gramzinski RA et al (1999) Synthetic oligodeoxynucleotides containing CpG motifs enhance immunogenicity of a peptide malaria vaccine in Aotus monkeys. Vaccine 17:3065–3071

    Article  CAS  PubMed  Google Scholar 

  127. Verthelyi D, Gursel M, Kenney RT et al (2003) CpG oligodeoxynucleotides protect normal and SIV-infected macaques from Leishmania infection. J Immunol 170:4717–4723

    Article  CAS  PubMed  Google Scholar 

  128. Verthelyi D, Wang VW, Lifson JD et al (2004) CpG oligodeoxynucleotides improve the response to hepatitis B immunization in healthy and SIV-infected rhesus macaques. AIDS 18:1003–1008

    Article  CAS  PubMed  Google Scholar 

  129. Diamant EP, Schechter C, Hodes DS et al (1993) Immunogenicity of hepatitis B vaccine in human immunodeficiency virus-infected children. Pediatr Infect Dis J 12:877–878

    Article  CAS  PubMed  Google Scholar 

  130. Wong EK, Bodsworth NJ, Slade MA et al (1996) Response to hepatitis B vaccination in a primary care setting: influence of HIV infection, CD4+ lymphocyte count and vaccination schedule. Int J STD AIDS 7:490–494

    Article  CAS  PubMed  Google Scholar 

  131. Pacanowski J, Kahi S, Baillet M et al (2001) Reduced blood CD123+ (lymphoid) and CD11c+ (myeloid) dendritic cell numbers in primary HIV-1 infection. Blood 98:3016–3021

    Article  CAS  PubMed  Google Scholar 

  132. Stern BV, Boehm BO, Tary-Lehmann M (2002) Vaccination with tumor peptide in CpG adjuvant protects via IFN-gamma-dependent CD4 cell immunity. J Immunol 168:6099–6105

    Article  CAS  PubMed  Google Scholar 

  133. Sandler AD, Chihara H, Kobayashi G et al (2003) CpG oligonucleotides enhance the tumor antigen-specific immune response of a granulocyte macrophage colony-stimulating factor-based vaccine strategy in neuroblastoma. Cancer Res 63:394–399

    CAS  PubMed  Google Scholar 

  134. Wille-Reece U, Flynn BJ, Lore K et al (2006) Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates. J Exp Med 203:1249–1258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Krieg AM (2006) Therapeutic potential of toll-like receptor 9 activation. Nat Rev Drug Discov 5:471–484

    Article  CAS  PubMed  Google Scholar 

  136. Rothenfusser S, Hornung V, Ayyoub M et al (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

    Article  CAS  PubMed  Google Scholar 

  137. Baines J, Celis E (2003) Immune-mediated tumor regression induced by CpG-containing oligodeoxynucleotides. Clin Cancer Res 9:2693–2700

    CAS  PubMed  Google Scholar 

  138. Tighe H, Takabayashi K, Schwartz D et al (2000) Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy Clin Immunol 106:124–134

    Article  CAS  PubMed  Google Scholar 

  139. Fourcade J, Kudela P, ndrade Filho PA et al (2008) Immunization with analog peptide in combination with CpG and montanide expands tumor antigen-specific CD8+ T cells in melanoma patients. J Immunother 31:781–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mukherjee P, Pathangey LB, Bradley JB et al (2007) MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model. Vaccine 25:1607–1618

    Article  CAS  PubMed  Google Scholar 

  141. Shirota Y, Shirota H, Klinman DM (2012) Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells. J Immunol 188:1592–1599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Sato-Kaneko F, Yao S, Ahmadi A et al (2017) Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer. JCI Insight 2:e93397

    Article  PubMed Central  Google Scholar 

  143. Wang S, Campos J, Gallotta M et al (2016) Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells. Proc Natl Acad Sci U S A 113:E7240–E7249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Shirota H, Klinman DM (2014) Recent progress concerning CpG DNA and its use as a vaccine adjuvant. Expert Rev Vaccines 13:299–312

    Article  CAS  PubMed  Google Scholar 

  145. Sacks T, Klinman DM (1997) Long-term effect of primary immunization on subsequent immune responsiveness. Cell Immunol 177:162–168

    Article  CAS  PubMed  Google Scholar 

  146. Cho HJ, Takabayashi K, Cheng PM et al (2000) Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism. Nat Biotechnol 18:509–514

    Article  CAS  PubMed  Google Scholar 

  147. Heit A, Schmitz F, O'Keeffe M et al (2005) Protective CD8 T cell immunity triggered by CpG-protein conjugates competes with the efficacy of live vaccines. J Immunol 174:4373–4380

    Article  CAS  PubMed  Google Scholar 

  148. Shirota H, Klinman DM (2011) CpG-conjugated apoptotic tumor cells elicit potent tumor-specific immunity. Cancer Immunol Immunother 60:659–669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Shirota H, Sano K, Hirasawa N et al (2001) Novel roles of CpG oligodeoxynucleotides as a leader for the sampling and presentation of CpG-tagged antigen by dendritic cells. J Immunol 167:66–74

    Article  CAS  PubMed  Google Scholar 

  150. Shirota H, Sano K, Hirasawa N et al (2002) B cells capturing antigen conjugated with CpG oligodeoxynucleotides induce Th1 cells by elaborating IL-12. J Immunol 169:787–794

    Article  CAS  PubMed  Google Scholar 

  151. Klinman DM, Sato T, Shimosato T (2016) Use of nanoparticles to deliver immunomodulatory oligonucleotides. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8:631–637

    Article  CAS  PubMed  Google Scholar 

  152. Wilson KD, Tam YK (2009) Lipid-based delivery of CpG oligodeoxynucleotides for cancer immunotherapy. Expert Rev Clin Pharmacol 2:181–193

    Article  CAS  PubMed  Google Scholar 

  153. Hanagata N (2012) Structure-dependent immunostimulatory effect of CpG oligodeoxynucleotides and their delivery system. Int J Nanomedicine 7:2181–2195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Heffernan MJ, Murthy N (2005) Polyketal nanoparticles: a new pH-sensitive biodegradable drug delivery vehicle. Bioconjug Chem 16:1340–1342

    Article  CAS  PubMed  Google Scholar 

  155. Fiore VF, Lofton MC, Roser-Page S et al (2010) Polyketal microparticles for therapeutic delivery to the lung. Biomaterials 31:810–817

    Article  CAS  PubMed  Google Scholar 

  156. Tada R, Muto S, Iwata T et al (2017) Attachment of class B CpG ODN onto DOTAP/DC-chol liposome in nasal vaccine formulations augments antigen-specific immune responses in mice. BMC Res Notes 10:68

    Article  PubMed  PubMed Central  Google Scholar 

  157. Shivahare R, Vishwakarma P, Parmar N et al (2014) Combination of liposomal CpG oligodeoxynucleotide 2006 and miltefosine induces strong cell-mediated immunity during experimental visceral leishmaniasis. PLoS One 9:e94596

    Article  PubMed  PubMed Central  Google Scholar 

  158. Puangpetch A, Anderson R, Huang YY et al (2012) Cationic liposomes extend the immunostimulatory effect of CpG oligodeoxynucleotide against Burkholderia pseudomallei infection in BALB/c mice. Clin Vaccine Immunol 19:675–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kim DH, Moon C, Oh SS et al (2015) Liposome-encapsulated CpG enhances antitumor activity accompanying the changing of lymphocyte populations in tumor via intratumoral administration. Nucleic Acid Ther 25:95–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lu Y, Wang Y, Miao L et al (2016) Exploiting in situ antigen generation and immune modulation to enhance chemotherapy response in advanced melanoma: a combination nanomedicine approach. Cancer Lett 379:32–38

    Article  CAS  PubMed  Google Scholar 

  161. Mansourian M, Badiee A, Jalali SA et al (2014) Effective induction of anti-tumor immunity using p5 HER-2/neu derived peptide encapsulated in fusogenic DOTAP cationic liposomes co-administrated with CpG-ODN. Immunol Lett 162:87–93

    Article  CAS  PubMed  Google Scholar 

  162. Krieg AM, Efler SM, Wittpoth M et al (2004) Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J Immunother 27:460–471

    Article  CAS  PubMed  Google Scholar 

  163. Scheiermann J, Klinman DM (2014) Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer. Vaccine 32:6377–6389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhu Q, Talton J, Zhang G et al (2012) Large intestine-targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection. Nat Med 18:1291–1296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Yamamoto H, Wu X, Nakanishi H et al (2015) A glucose carbonate apatite complex exhibits in vitro and in vivo anti-tumour effects. Sci Rep 5:7742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Wang Y, Yamamoto Y, Shigemori S et al (2015) Inhibitory/suppressive oligodeoxynucleotide nanocapsules as simple oral delivery devices for preventing atopic dermatitis in mice. Mol Ther 23:297–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Alexopoulou L, Holt AC, Medzhitov R et al (2001) Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3. Nature 413:732–738

    Article  CAS  PubMed  Google Scholar 

  168. Hoebe K, Janssen EM, Kim SO et al (2003) Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat Immunol 4:1223–1229

    Article  CAS  PubMed  Google Scholar 

  169. Tross D, Petrenko L, Klaschik S et al (2009) Global changes in gene expression and synergistic interactions induced by TLR9 and TLR3. Mol Immunol 46:2557–2564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Zheng R, Cohen PA, Paustian CA et al (2008) Paired toll-like receptor agonists enhance vaccine therapy through induction of interleukin-12. Cancer Res 68:4045–4049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Whitmore MM, DeVeer MJ, Edling A et al (2004) Synergistic activation of innate immunity by double-stranded RNA and CpG DNA promotes enhanced antitumor activity. Cancer Res 64:5850–5860

    Article  CAS  PubMed  Google Scholar 

  172. He H, Genovese KJ, Nisbet DJ et al (2007) Synergy of CpG oligodeoxynucleotide and double-stranded RNA (poly I:C) on nitric oxide induction in chicken peripheral blood monocytes. Mol Immunol 44:3234–3242

    Article  CAS  PubMed  Google Scholar 

  173. Zhu Q, Egelston C, Gagnon S et al (2010) Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice. J Clin Invest 120:607–616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Bayyurt B, Tincer G, Almacioglu K et al (2017) Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development. J Control Release 247:134–144

    Article  CAS  PubMed  Google Scholar 

  175. Cluff CW (2010) Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines: clinical results. Adv Exp Med Biol 667:111–123

    Article  PubMed  Google Scholar 

  176. Kruit WH, Suciu S, Dreno B et al (2013) Selection of immunostimulant AS15 for active immunization with MAGE-A3 protein: results of a randomized phase II study of the European Organisation for Research and Treatment of Cancer melanoma Group in Metastatic Melanoma. J Clin Oncol 31:2413–2420

    Article  CAS  PubMed  Google Scholar 

  177. Hamilton E, Blackwell K, Hobeika AC et al (2012) Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected]. J Transl Med 10:28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zhao BG, Vasilakos JP, Tross D et al (2014) Combination therapy targeting toll like receptors 7, 8 and 9 eliminates large established tumors. J Immunother Cancer 2:12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Shirota H, Tross D, Klinman DM (2015) CpG oligonucleotides as cancer vaccine adjuvants. Vaccines (Basel) 3:390–407

    Article  CAS  Google Scholar 

  180. Temizoz B, Kuroda E, Ohata K et al (2015) TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN. Eur J Immunol 45:1159–1169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Cooper CL, Davis HL, Morris ML et al (2004) CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study. J Clin Immunol 24:693–701

    Article  CAS  PubMed  Google Scholar 

  182. Halperin SA, Van NG, Smith B et al (2003) A phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Vaccine 21:2461–2467

    Article  CAS  PubMed  Google Scholar 

  183. Rynkiewicz D, Rathkopf M, Sim I et al (2011) Marked enhancement of the immune response to BioThrax(R) (anthrax vaccine adsorbed) by the TLR9 agonist CPG 7909 in healthy volunteers. Vaccine 29:6313–6320

    Article  CAS  PubMed  Google Scholar 

  184. 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

    Article  CAS  PubMed  Google Scholar 

  185. Speiser DE, Lienard D, Rufer N et al (2005) Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 115:739–746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Ioannou XP, Griebel P, Hecker R et al (2002) The immunogenicity and protective efficacy of bovine herpesvirus 1 glycoprotein D plus Emulsigen are increased by formulation with CpG oligodeoxynucleotides. J Virol 76:9002–9010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Ioannou XP, Gomis SM, Karvonen B et al (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

    Article  CAS  PubMed  Google Scholar 

  188. Hirunpetcharat C, Wipasa J, Sakkhachornphop S et al (2003) CpG oligodeoxynucleotide enhances immunity against blood-stage malaria infection in mice parenterally immunized with a yeast-expressed 19 kDa carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein-1 (MSP1(19) formulated in oil-based Montanides). Vaccine 21:2923–2932

    Article  CAS  PubMed  Google Scholar 

  189. Kumar S, Jones TR, Oakley MS et al (2004) CpG oligodeoxynucleotide and Montanide ISA 51 adjuvant combination enhanced the protective efficacy of a subunit malaria vaccine. Infect Immun 72:949–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Adamus T, Kortylewski M (2018) The revival of CpG oligonucleotide-based cancer immunotherapies6. Contemp Oncol (Pozn) 22:56–60

    Google Scholar 

  191. Hu-Lieskovan S, Ribas A (2017) New combination strategies using programmed cell death 1/programmed cell death ligand 1 checkpoint inhibitors as a backbone. Cancer J 23:10–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Davila E, Kennedy R, Celis E (2003) Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade. Cancer Res 63:3281–3288

    CAS  PubMed  Google Scholar 

  193. Mangsbo SM, Sandin LC, Anger K et al (2010) Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy. J Immunother 33:225–235

    Article  CAS  PubMed  Google Scholar 

  194. Lavanchy D (2004) Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 11:97–107

    Article  CAS  PubMed  Google Scholar 

  195. Walayat S, Ahmed Z, Martin D et al (2015) Recent advances in vaccination of non-responders to standard dose hepatitis B virus vaccine. World J Hepatol 7:2503–2509

    Article  PubMed  PubMed Central  Google Scholar 

  196. Denis F, Mounier M, Hessel L et al (1984) Hepatitis-B vaccination in the elderly. J Infect Dis 149:1019

    Article  CAS  PubMed  Google Scholar 

  197. de RS, Heijtink RA, Bakker-Bendik M et al (1994) Immunogenicity of standard and low dose vaccination using yeast-derived recombinant hepatitis B surface antigen in elderly volunteers. Vaccine 12:532–534

    Article  Google Scholar 

  198. Agarwal SK, Irshad M, Dash SC (1999) Comparison of two schedules of hepatitis B vaccination in patients with mild, moderate and severe renal failure. J Assoc Physicians India 47:183–185

    CAS  PubMed  Google Scholar 

  199. Mattos AA, Gomes EB, Tovo CV et al (2004) Hepatitis B vaccine efficacy in patients with chronic liver disease by hepatitis C virus. Arq Gastroenterol 41:180–184

    Article  PubMed  Google Scholar 

  200. Freed DC, Towne VM, Casimiro DR et al (2011) Evaluating functional antibodies in rhesus monkeys immunized with hepatitis B virus surface antigen vaccine with novel adjuvant formulations. Vaccine 29:9385–9390

    Article  CAS  PubMed  Google Scholar 

  201. Bai JY, Yang YT, Zhu R et al (2012) CpG oligodeoxynucleotides discriminately enhance binding capacity of human naive B cells to hepatitis B virus epitopes. Can J Microbiol 58:752–759

    Article  CAS  PubMed  Google Scholar 

  202. Wang S, Han Q, Zhang G et al (2011) CpG oligodeoxynucleotide-adjuvanted fusion peptide derived from HBcAg epitope and HIV-tat may elicit favorable immune response in PBMCs from patients with chronic HBV infection in the immunotolerant phase. Int Immunopharmacol 11:406–411

    Article  CAS  PubMed  Google Scholar 

  203. Kuan RK, Janssen R, Heyward W et al (2013) Cost-effectiveness of hepatitis B vaccination using HEPLISAV in selected adult populations compared to Engerix-B(R) vaccine. Vaccine 31:4024–4032

    Article  PubMed  Google Scholar 

  204. Eng NF, Bhardwaj N, Mulligan R et al (2013) The potential of 1018 ISS adjuvant in hepatitis B vaccines: HEPLISAV review. Hum Vaccin Immunother 9:1661–1672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Cooper C, Mackie D (2011) Hepatitis B surface antigen-1018 ISS adjuvant-containing vaccine: a review of HEPLISAV safety and efficacy. Expert Rev Vaccines 10:417–427

    Article  CAS  PubMed  Google Scholar 

  206. Heyward WL, Kyle M, Blumenau J et al (2013) Immunogenicity and safety of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40–70 years of age. Vaccine 31:5300–5305

    Article  CAS  PubMed  Google Scholar 

  207. Jackson S, Lentino J, Kopp J et al (2018) Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults. Vaccine 36:668–674

    Article  CAS  PubMed  Google Scholar 

  208. Kamal SM, Rashid AK, Bakar MA et al (2011) Anthrax: an update. Asian Pac J Trop Biomed 1:496–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Geier DA, Geier MR (2002) Anthrax vaccination and joint related adverse reactions in light of biological warfare scenarios. Clin Exp Rheumatol 20:217–220

    CAS  PubMed  Google Scholar 

  210. Ready T (2004) US soldiers refuse to fall in line with anthrax vaccination scheme. Nat Med 10:112

    Article  CAS  PubMed  Google Scholar 

  211. Tross D, Klinman DM (2008) Effect of CpG oligonucleotides on vaccine-induced B cell memory. J Immunol 181:5785–5790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Hopkins RJ, Daczkowski NF, Kaptur PE et al (2013) Randomized, double-blind, placebo-controlled, safety and immunogenicity study of 4 formulations of anthrax vaccine adsorbed plus CPG 7909 (AV7909) in healthy adult volunteers. Vaccine 31:3051–3058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Gupta S, Gunter JT, Novak RJ et al (2009) Patterns of plasmodium vivax and Plasmodium falciparum malaria underscore importance of data collection from private health care facilities in India. Malar J 8:227

    Article  PubMed  PubMed Central  Google Scholar 

  214. Ellis RD, Sagara I, Doumbo O et al (2010) Blood stage vaccines for Plasmodium falciparum: current status and the way forward. Hum Vaccin 6:627–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Ellis RD, Martin LB, Shaffer D et al (2010) Phase 1 trial of the Plasmodium falciparum blood stage vaccine MSP1(42)-C1/Alhydrogel with and without CPG 7909 in malaria naive adults. PLoS One 5:e8787

    Article  PubMed  PubMed Central  Google Scholar 

  216. Dicko A, Diemert DJ, Sagara I et al (2007) Impact of a Plasmodium falciparum AMA1 vaccine on antibody responses in adult Malians. PLoS One 2:e1045

    Article  PubMed  PubMed Central  Google Scholar 

  217. Sagara I, Ellis RD, Dicko A et al (2009) A randomized and controlled phase 1 study of the safety and immunogenicity of the AMA1-C1/Alhydrogel + CPG 7909 vaccine for Plasmodium falciparum malaria in semi-immune Malian adults. Vaccine 27:7292–7298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Crompton PD, Mircetic M, Weiss G et al (2009) The TLR9 ligand CpG promotes the acquisition of Plasmodium falciparum-specific memory B cells in malaria-naive individuals. J Immunol 182:3318–3326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Mullen GE, Ellis RD, Miura K et al (2008) Phase 1 trial of AMA1-C1/Alhydrogel plus CPG 7909: an asexual blood-stage vaccine for Plasmodium falciparum malaria. PLoS One 3:e2940

    Article  PubMed  PubMed Central  Google Scholar 

  220. Duncan CJ, Sheehy SH, Ewer KJ et al (2011) Impact on malaria parasite multiplication rates in infected volunteers of the protein-in-adjuvant vaccine AMA1-C1/Alhydrogel+CPG 7909. PLoS One 6:e22271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  222. Rhee JW, Kim D, Park BK et al (2012) 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 7:e48750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Fang Y, Rowe T, Leon AJ et al (2010) Molecular characterization of in vivo adjuvant activity in ferrets vaccinated against influenza virus. J Virol 84:8369–8388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Lopez-Palomo C, Martin-Zamorano M, Benitez E et al (2004) Pneumonia in HIV-infected patients in the HAART era: incidence, risk, and impact of the pneumococcal vaccination. J Med Virol 72:517–524

    Article  CAS  PubMed  Google Scholar 

  225. Hersperger AR, Pereyra F, Nason M et al (2010) Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathog 6:e1000917

    Article  PubMed  PubMed Central  Google Scholar 

  226. Agrawal S, Agrawal A, Doughty B et al (2003) Cutting edge: different toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J Immunol 171:4984–4989

    Article  CAS  PubMed  Google Scholar 

  227. Scheller C, Ullrich A, McPherson K et al (2004) CpG oligodeoxynucleotides activate HIV replication in latently infected human T cells. J Biol Chem 279:21897–21902

    Article  CAS  PubMed  Google Scholar 

  228. Equils O, Schito ML, Karahashi H et al (2003) Toll-like receptor 2 (TLR2) and TLR9 signaling results in HIV-long terminal repeat trans-activation and HIV replication in HIV-1 transgenic mouse spleen cells: implications of simultaneous activation of TLRs on HIV replication. J Immunol 170:5159–5164

    Article  CAS  PubMed  Google Scholar 

  229. Sulkowski MS, Chaisson RE, Karp CL et al (1998) The effect of acute infectious illnesses on plasma human immunodeficiency virus (HIV) type 1 load and the expression of serologic markers of immune activation among HIV-infected adults. J Infect Dis 178:1642–1648

    Article  CAS  PubMed  Google Scholar 

  230. Rotchford K, Strum AW, Wilkinson D (2000) Effect of coinfection with STDs and of STD treatment on HIV shedding in genital-tract secretions: systematic review and data synthesis. Sex Transm Dis 27:243–248

    Article  CAS  PubMed  Google Scholar 

  231. Cooper CL, Davis HL, Angel JB et al (2005) CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 19:1473–1479

    Article  CAS  PubMed  Google Scholar 

  232. Angel JB, Cooper CL, Clinch J et al (2008) CpG increases vaccine antigen-specific cell-mediated immunity when administered with hepatitis B vaccine in HIV infection. J Immune Based Ther Vaccines 6:4

    Article  PubMed  PubMed Central  Google Scholar 

  233. Cooper CL, Angel JB, Seguin I et al (2008) CPG 7909 adjuvant plus hepatitis B virus vaccination in HIV-infected adults achieves long-term seroprotection for up to 5 years. Clin Infect Dis 46:1310–1314

    Article  CAS  PubMed  Google Scholar 

  234. Sogaard OS, Lohse N, Harboe ZB et al (2010) Improving the immunogenicity of pneumococcal conjugate vaccine in HIV-infected adults with a toll-like receptor 9 agonist adjuvant: a randomized, controlled trial. Clin Infect Dis 51:42–50

    Article  PubMed  Google Scholar 

  235. Winckelmann AA, Munk-Petersen LV, Rasmussen TA et al (2013) Administration of a Toll-like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-infected patients. PLoS One 8:e62074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Creticos PS, Schroeder JT, Hamilton RG et al (2006) Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 355:1445–1455

    Article  CAS  PubMed  Google Scholar 

  237. Simons FE, Shikishima Y, Van NG et al (2004) Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J Allergy Clin Immunol 113:1144–1151

    Article  CAS  PubMed  Google Scholar 

  238. Kundig TM, Klimek L, Schendzielorz P et al (2015) Is the allergen really needed in allergy immunotherapy? Curr Treat Options Allergy 2:72–82

    Article  PubMed  Google Scholar 

  239. Senti G, Johansen P, Haug S et al (2009) Use of A-type CpG oligodeoxynucleotides as an adjuvant in allergen-specific immunotherapy in humans: a phase I/IIa clinical trial. Clin Exp Allergy 39:562–570

    Article  CAS  PubMed  Google Scholar 

  240. Klimek L, Willers J, Hammann-Haenni A et al (2011) Assessment of clinical efficacy of CYT003-QbG10 in patients with allergic rhinoconjunctivitis: a phase IIb study. Clin Exp Allergy 41:1305–1312

    Article  CAS  PubMed  Google Scholar 

  241. Vasievich EA, Huang L (2011) The suppressive tumor microenvironment: a challenge in cancer immunotherapy. Mol Pharm 8:635–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Zoglmeier C, Bauer H, Noerenberg D et al (2011) CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice. Clin Cancer Res 17:1765–1775

    Article  CAS  PubMed  Google Scholar 

  244. Krieg AM (2004) Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 6:88–95

    Article  PubMed  Google Scholar 

  245. Carpentier AF, Chen L, Maltonti F et al (1999) Oligodeoxynucleotides containing CpG motifs can induce rejection of a neuroblastoma in mice. Cancer Res 59:5429–5432

    CAS  PubMed  Google Scholar 

  246. Carpentier AF, Xie J, Mokhtari K et al (2000) Successful treatment of intracranial gliomas in rat by oligodeoxynucleotides containing CpG motifs. Clin Cancer Res 6:2469–2473

    CAS  PubMed  Google Scholar 

  247. Brody JD, Ai WZ, Czerwinski DK et al (2010) In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol 28:4324–4332

    Article  PubMed  PubMed Central  Google Scholar 

  248. Hofmann MA, Kors C, Audring H et al (2008) Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma. J Immunother 31:520–527

    Article  CAS  PubMed  Google Scholar 

  249. Molenkamp BG, Sluijter BJ, Van Leeuwen PA et al (2008) Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients. Clin Cancer Res 14:4532–4542

    Article  CAS  PubMed  Google Scholar 

  250. Kim YH, Gratzinger D, Harrison C et al (2012) In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 119:355–363

    Article  PubMed  PubMed Central  Google Scholar 

  251. Carson WE III, Shapiro CL, Crespin TR et al (2004) Cellular immunity in breast cancer patients completing taxane treatment. Clin Cancer Res 10:3401–3409

    Article  CAS  PubMed  Google Scholar 

  252. Lake RA, Robinson BW (2005) Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer 5:397–405

    Article  CAS  PubMed  Google Scholar 

  253. Carpentier A, Laigle-Donadey F, Zohar S et al (2006) Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro-Oncology 8:60–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Manegold C, Gravenor D, Woytowitz D et al (2008) Randomized phase II trial of a toll-like receptor 9 agonist oligodeoxynucleotide, PF-3512676, in combination with first-line taxane plus platinum chemotherapy for advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3979–3986

    Article  CAS  PubMed  Google Scholar 

  255. Friedberg JW, Kim H, McCauley M et al (2005) Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-alpha/beta-inducible gene expression, without significant toxicity. Blood 105:489–495

    Article  CAS  PubMed  Google Scholar 

  256. Leonard JP, Link BK, Emmanouilides C et al (2007) Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non-Hodgkin's lymphoma. Clin Cancer Res 13:6168–6174

    Article  CAS  PubMed  Google Scholar 

  257. Friedberg JW, Kelly JL, Neuberg D et al (2009) Phase II study of a TLR-9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma. Br J Haematol 146:282–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Baumgaertner P, Jandus C, Rivals JP et al (2012) Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int J Cancer 130:2607–2617

    Article  CAS  PubMed  Google Scholar 

  259. Bioley G, Guillaume P, Luescher I et al (2009) Vaccination with a recombinant protein encoding the tumor-specific antigen NY-ESO-1 elicits an A2/157-165-specific CTL repertoire structurally distinct and of reduced tumor reactivity than that elicited by spontaneous immune responses to NY-ESO-1-expressing tumors. J Immunother 32:161–168

    Article  CAS  PubMed  Google Scholar 

  260. Valmori D, Souleimanian NE, Tosello V et al (2007) Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming. Proc Natl Acad Sci U S A 104:8947–8952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. McQuade JL, Homsi J, Torres-Cabala CA et al (2018) A phase II trial of recombinant MAGE-A3 protein with immunostimulant AS15 in combination with high-dose Interleukin-2 (HDIL2) induction therapy in metastatic melanoma. BMC Cancer 18:1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Haining WN, Davies J, Kanzler H et al (2008) CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans. Clin Cancer Res 14:5626–5634

    Article  CAS  PubMed  Google Scholar 

  263. Tarhini AA, Leng S, Moschos SJ et al (2012) Safety and immunogenicity of vaccination with MART-1 (26-35, 27L), gp100 (209-217, 210M), and tyrosinase (368-376, 370D) in adjuvant with PF-3512676 and GM-CSF in metastatic melanoma. J Immunother 35:359–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Del VM, Di GL, Ascierto PA et al (2014) Efficacy and safety of ipilimumab 3mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer 50:121–127

    Article  Google Scholar 

  265. McCluskie MJ, Weeratna RD, Davis HL (2000) The role of CpG in DNA vaccines. Springer Semin Immunopathol 22:125–132

    Article  CAS  PubMed  Google Scholar 

  266. Klinman DM (2003) CpG DNA as a vaccine adjuvant. Expert Rev Vaccines 2:305–315

    Article  CAS  PubMed  Google Scholar 

  267. Hobernik D, Bros M (2018) DNA vaccines-how far from clinical use? Int J Mol Sci 19:3605

    Article  PubMed Central  Google Scholar 

  268. Prazeres DMF, Monteiro GA (2014) Plasmid Biopharmaceuticals. Microbiol Spectr 2

    Google Scholar 

  269. Ferraro B, Morrow MP, Hutnick NA et al (2011) Clinical applications of DNA vaccines: current progress. Clin Infect Dis 53:296–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Tang DC, DeVit M, Johnston SA (1992) Genetic immunization is a simple method for eliciting an immune response. Nature 356:152–154

    Article  CAS  PubMed  Google Scholar 

  271. Ulmer JB, Donnelly JJ, Parker SE et al (1993) Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259:1745–1749

    Article  CAS  PubMed  Google Scholar 

  272. Wang B, Agadjanyan MG, Srikantan V et al (1993) Molecular cloning, expression, and biological characterization of an HTLV-II envelope glycoprotein: HIV-1 expression is permissive for HTLV-II-induced cell fusion. AIDS Res Hum Retrovir 9:849–860

    Article  CAS  PubMed  Google Scholar 

  273. Fynan EF, Webster RG, Fuller DH et al (1993) DNA vaccines: protective immunizations by parenteral, mucosal, and gene-gun inoculations. Proc Natl Acad Sci U S A 90:11478–11482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Klinman DM, Klaschik S, Tross D et al (2010) FDA guidance on prophylactic DNA vaccines: analysis and recommendations. Vaccine 28:2801–2805

    Article  PubMed  Google Scholar 

  275. Dauphin G, Zientara S (2007) West Nile virus: recent trends in diagnosis and vaccine development. Vaccine 25:5563–5576

    Article  CAS  PubMed  Google Scholar 

  276. Witter MP, Groenewegen HJ, Lopes da Silva FH et al (1989) Functional organization of the extrinsic and intrinsic circuitry of the parahippocampal region. Prog Neurobiol 33:161–253

    Article  CAS  PubMed  Google Scholar 

  277. Krieg AM, Wu T, Weeratna R et al (1998) Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci U S A 95:12631–12636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Sato Y, Roman M, Tighe H et al (1996) Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273:352–354

    Article  CAS  PubMed  Google Scholar 

  279. Kojima Y, Xin KQ, Ooki T et al (2002) Adjuvant effect of multi-CpG motifs on an HIV-1 DNA vaccine. Vaccine 20:2857–2865

    Article  CAS  PubMed  Google Scholar 

  280. Schneeberger A, Wagner C, Zemann A et al (2004) CpG motifs are efficient adjuvants for DNA cancer vaccines. J Invest Dermatol 123:371–379

    Article  CAS  PubMed  Google Scholar 

  281. Ma Y, Jiao YY, Yu YZ et al (2018) A built-in CpG adjuvant in RSV F protein DNA vaccine drives a Th1 polarized and enhanced protective immune response. Viruses 10:38

    Article  PubMed Central  Google Scholar 

  282. Trimble CL, Morrow MP, Kraynyak KA et al (2015) Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet 386:2078–2088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Kim TJ, Jin HT, Hur SY et al (2014) Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients. Nat Commun 5:5317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Tiriveedhi V, Tucker N, Herndon J et al (2014) Safety and preliminary evidence of biologic efficacy of a mammaglobin-a DNA vaccine in patients with stable metastatic breast cancer. Clin Cancer Res 20:5964–5975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Heikenwalder M, Polymenidou M, Junt T et al (2004) Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med 10:187–192

    Article  CAS  PubMed  Google Scholar 

  286. Sparwasser T, Hultner L, Koch ES et al (1999) Immunostimulatory CpG-oligodeoxynucleotides cause extramedullary murine hemopoiesis. J Immunol 162:2368–2374

    Article  CAS  PubMed  Google Scholar 

  287. Le HC, Cohen P, Bousser MG et al (1999) Suspected hepatitis B vaccination related vasculitis. J Rheumatol 26:191–194

    Google Scholar 

  288. Allen MB, Cockwell P, Page RL (1993) Pulmonary and cutaneous vasculitis following hepatitis B vaccination. Thorax 48:580–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Gilkeson GS, Ruiz P, Howell D et al (1993) Induction of immune-mediated glomerulonephritis in normal mice immunized with bacterial DNA. Clin Immunol Immunopathol 68:283–292

    Article  CAS  PubMed  Google Scholar 

  290. Steinberg AD, Krieg AM, Gourley MF et al (1990) Theoretical and experimental approaches to generalized autoimmunity. Immunol Rev 118:129–163

    Article  CAS  PubMed  Google Scholar 

  291. Gilkeson GS, Pippen AM, Pisetsky DS (1995) Induction of cross-reactive anti-dsDNA antibodies in preautoimmune NZB/NZW mice by immunization with bacterial DNA. J Clin Invest 95:1398–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Gilkeson GS, Conover J, Halpern M et al (1998) Effects of bacterial DNA on cytokine production by (NZB/NZW)F1 mice. J Immunol 161:3890–3895

    Article  CAS  PubMed  Google Scholar 

  293. Mor G, Singla M, Steinberg AD et al (1997) Do DNA vaccines induce autoimmune disease? Hum Gene Ther 8:293–300

    Article  CAS  PubMed  Google Scholar 

  294. Segal BM, Klinman DM, Shevach EM (1997) Microbial products induce autoimmune disease by an IL-12-dependent pathway. J Immunol 158:5087–5090

    Article  CAS  PubMed  Google Scholar 

  295. Segal BM, Chang JT, Shevach EM (2000) CpG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo. J Immunol 164:5683–5688

    Article  CAS  PubMed  Google Scholar 

  296. Bachmaier K, Meu N, Maza LM (1999) Chlamydia infections and heart disease linked through antigenic mimicry. Science 283:1335–1339

    Article  CAS  PubMed  Google Scholar 

  297. Zeuner RA, Verthelyi D, Gursel M et al (2003) Influence of stimulatory and suppressive DNA motifs on host susceptibility to inflammatory arthritis. Arthritis Rheum 48:1701–1707

    Article  CAS  PubMed  Google Scholar 

  298. Ellis RD, Mullen GE, Pierce M et al (2009) A phase 1 study of the blood-stage malaria vaccine candidate AMA1-C1/Alhydrogel with CPG 7909, using two different formulations and dosing intervals. Vaccine 27:4104–4109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Yi AK, Hornbeck P, Lafrenz DE et al (1996) CpG DNA rescue of murine B lymphoma cells from anti-IgM-induced growth arrest and programmed cell death is associated with increased expression of c-myc and bcl-xL1. J Immunol 157:4918–4925

    Article  CAS  PubMed  Google Scholar 

  300. Krieg AM, Vollmer J (2007) Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol Rev 220:251–269

    Article  CAS  PubMed  Google Scholar 

  301. Yu P, Musette P, Peng SL (2008) Toll-like receptor 9 in murine lupus: more friend than foe! Immunobiology 213:151–157

    Article  CAS  PubMed  Google Scholar 

  302. Carpentier A, Metellus P, Ursu R et al (2010) Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro-Oncology 12:401–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Splawn LM, Bailey CA, Medina JP et al (2018) Heplisav-B vaccination for the prevention of hepatitis B virus infection in adults in the United States. Drugs Today (Barc) 54:399–405

    Article  CAS  Google Scholar 

  304. Madan RA, Bilusic M, Heery C et al (2012) Clinical evaluation of TRICOM vector therapeutic cancer vaccines. Semin Oncol 39:296–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Cancer Institute, NIH, Frederick, MD, USA

    Neslihan Kayraklioglu, Begum Horuluoglu & Dennis M. Klinman

  2. Leitman Klinman Consulting, Potomac, MD, USA

    Dennis M. Klinman

Authors
  1. Neslihan Kayraklioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Begum Horuluoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dennis M. Klinman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dennis M. Klinman .

Editor information

Editors and Affiliations

  1. CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal

    Ângela Sousa

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Kayraklioglu, N., Horuluoglu, B., Klinman, D.M. (2021). CpG Oligonucleotides as Vaccine Adjuvants. In: Sousa, Â. (eds) DNA Vaccines. Methods in Molecular Biology, vol 2197. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0872-2_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-0872-2_4

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0871-5

  • Online ISBN: 978-1-0716-0872-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation