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Expert Review of Vaccines Volume 13, 2014 - Issue 2
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Reviews

Recent progress concerning CpG DNA and its use as a vaccine adjuvant

Hidekazu ShirotaDepartment of Clinical Oncology, Tohoku University, Japan
&
Dennis M KlinmanCancer and Inflammation Program, National Cancer Institute, Bldg 567 Rm 205 NCI in Frederick, Frederick, MD 21702, USACorrespondence[email protected]
Pages 299-312 | Published online: 26 Nov 2013

References

  • Janeway C Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).
  • Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86(6), 973–983 (1996).
  • Poltorak A, He X, Smirnova I et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396), 2085–2088 (1998).
  • Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).
  • Akira S, Takeda K. Toll-like receptor signalling. Nat. Rev. Immunol. 4(7), 499–511 (2004).
  • Kanzler H, Barrat FJ, Hessel EM, Coffman RL. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat. Med. 13(5), 552–559 (2007).
  • Lorne E, Dupont H, Abraham E. Toll-like receptors 2 and 4: initiators of non-septic inflammation in critical care medicine? Intensive Care Med. 36(11), 1826–1835 (2010).
  • Redecke V, Hacker H, Datta SK et al. Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J. Immunol. 172(5), 2739–2743 (2004).
  • Dabbagh K, Dahl ME, Stepick-Biek P, Lewis DB. Toll-like receptor 4 is required for optimal development of Th2 immune responses: role of dendritic cells. J. Immunol. 168(9), 4524–4530 (2002).
  • Krieg AM, Homan LL, Yi AK, Harty JT. CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J. Immunol. 161, 2428–2434 (1998).
  • Elkins KL, Rhinehart-Jones TR, Stibitz S, Conover JS, Klinman DM. Bacterial DNA containing CpG motifs stimulates lymphocyte-dependent protection of mice against lethal infection with intracellular bacteria. J. Immunol. 162, 2291–2298 (1999).
  • Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat. Rev. Immunol. 4(4), 249–258 (2004).
  • Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5(12), 1219–1226 (2004).
  • Kadowaki N, Ho S, Antonenko S et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194(6), 863–869 (2001).
  • Kadowaki N, Liu YJ. Natural type I interferon-producing cells as a link between innate and adaptive immunity. Hum. Immunol. 63(12), 1126–1132 (2002).
  • Cho HJ, Hayashi T, Datta SK et al. IFN-alpha beta promote priming of antigen-specific CD8+ and CD4+ T lymphocytes by immunostimulatory DNA-based vaccines. J. Immunol. 168(10), 4907–4913 (2002).
  • Ahonen CL, Doxsee CL, McGurran SM et al. Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN. J. Exp. Med. 199(6), 775–784 (2004).
  • Shirota H, Sano K, Kikuchi T, Tamura G, Shirato K. 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(2), 176–182 (2000).
  • Shirota H, Sano K, Kikuchi T, Tamura G, Shirato K. Regulation of murine airway eosinophilia and Th2 cells by antigen-conjugated CpG oligodeoxynucleotides as a novel antigen-specific immunomodulator. J. Immunol. 164(11), 5575–5582 (2000).
  • Latz E, Schoenemeyer A, Visintin A et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5(2), 190–198 (2004).
  • Barton GM, Kagan JC, Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat. Immunol. 7(1), 49–56 (2006).
  • Mouchess ML, Arpaia N, Souza G et al. Transmembrane mutations in Toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation. Immunity 35(5), 721–732 (2011).
  • Lande R, Gregorio J, Facchinetti V et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449(7162), 564–569 (2007).
  • Barrat FJ, Meeker T, Gregorio J et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202(8), 1131–1139 (2005).
  • Tewary P, de la RG, Sharma N et al. beta-Defensin 2 and 3 promote the uptake of self or CpG DNA, enhance IFN-alpha production by human plasmacytoid dendritic cells, and promote inflammation. J. Immunol. 191(2), 865–874 (2013).
  • Park B, Brinkmann MM, Spooner E, Lee CC, Kim YM, Ploegh HL. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat. Immunol. 9(12), 1407–1414 (2008).
  • Ewald SE, Lee BL, Lau L et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456(7222), 658–662 (2008).
  • Sepulveda FE, Maschalidi S, Colisson R et al. Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. Immunity 31(5), 737–748 (2009).
  • Ewald SE, Engel A, Lee J, Wang M, Bogyo M, Barton GM. Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J. Exp. Med. 208(4), 643–651 (2011).
  • Mutwiri GK, Nichani AK, Babiuk S, Babiuk LA. Strategies for enhancing the immunostimulatory effects of CpG oligodeoxynucleotides. J. Control. Release 97(1), 1–17 (2004).
  • Verthelyi D, Ishii KJ, Gursel M, Takeshita F, Klinman DM. Human peripheral blood cells differentially recognize and respond to two distinct CpG motifs. J. Immunol. 166, 2372–2377 (2001).
  • Hartmann G, Battiany J, Poeck H et al. Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells. Eur. J. Immunol. 33(6), 1633–1641 (2003).
  • Krug A, Rothenfusser S, Hornung V et al. Identification of CpG oligonucleotide sequences with high induction of IFNa/b in plasmacytoid dendritic cells. Eur. J. Immunol. 31, 2154–2163 (2001).
  • Ballas ZK, Rasmussen WL, Krieg AM. Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J. Immunol. 157, 1840–1847 (1996).
  • Guiducci C, Ott G, Chan JH et al. Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J. Exp. Med. 203(8), 1999–2008 (2006).
  • Honda K, Ohba Y, Yanai H et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434(7036), 1035–1040 (2005).
  • Storni T, Ruedl C, Schwarz K, Schwendener RA, Renner WA, Bachmann MF. Nonmethylated CG motifs packaged into virus-like particles induce protective cytotoxic T cell responses in the absence of systemic side effects. J. Immunol. 172(3), 1777–1785 (2004).
  • Marshall JD, Fearon K, Abbate C et al. Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions. J. Leukoc. Biol. 73(6), 781–792 (2003).
  • Vollmer J, Krieg AM. Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Adv. Drug Deliv. Rev. 61 (3), 195–204 (2009)
  • Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5(10), 987–995 (2004).
  • Hartmann G, Weeratna RD, Ballas ZK et al. Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J. Immunol. 164, 1617–1624 (2000).
  • Bernasconi NL, Onai N, Lanzavecchia A. 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(11), 4500–4504 (2003).
  • Eckl-Dorna J, Batista FD. BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation. Blood 113(17), 3969–3977 (2009).
  • Agnello D, Lankford CS, Bream J et al. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J. Clin. Immunol. 23(3), 147–161 (2003).
  • Kuwajima S, Sato T, Ishida K, Tada H, Tezuka H, Ohteki T. Interleukin 15-dependent crosstalk between conventional and plasmacytoid dendritic cells is essential for CpG-induced immune activation. Nat. Immunol. 7(7), 740–746 (2006).
  • Gerosa F, Gobbi A, Zorzi P et al. The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J. Immunol. 174, 727–734 (2005).
  • Sacks T, Klinman DM. Long-term effect of primary immunization on subsequent immune responsiveness. Cell. Immunol. 177, 162–168 (1997).
  • Cho HJ, Takabayashi K, Cheng PM et al. Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism. Nat. Biotechnol. 18, 509–514. (2000).
  • Heit A, Schmitz F, O’Keeffe M et al. Protective CD8 T cell immunity triggered by CpG-protein conjugates competes with the efficacy of live vaccines. J. Immunol. 174(7), 4373–4380 (2005).
  • Shirota H, Klinman DM. CpG-conjugated apoptotic tumor cells elicit potent tumor-specific immunity. Cancer Immunol. Immunother. 60(5), 659–669 (2011).
  • Shirota H, Sano K, Hirasawa N et al. Novel roles of CpG oligodeoxynucleotides as a leader for the sampling and presentation of CpG-tagged antigen by dendritic cells. J. Immunol. 167(1), 66–74 (2001).
  • Shirota H, Sano K, Hirasawa N et al. B cells capturing antigen conjugated with CpG oligodeoxynucleotides induce Th1 cells by elaborating IL-12. J. Immunol. 169(2), 787–794 (2002).
  • Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413(6857), 732–738 (2001).
  • Hoebe K, Janssen EM, Kim SO et al. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat. Immunol. 4(12), 1223–1229 (2003).
  • Tross D, Petrenko L, Klaschik S, Zhu Q, Klinman DM. Global changes in gene expression and synergistic interactions induced by TLR9 and TLR3. Mol. Immunol. 46(13), 2557–2564 (2009).
  • Zheng R, Cohen PA, Paustian CA et al. Paired Toll-like receptor agonists enhance vaccine therapy through induction of interleukin-12. Cancer Res. 68(11), 4045–4049 (2008).
  • Whitmore MM, DeVeer MJ, Edling A et al. Synergistic activation of innate immunity by double-stranded RNA and CpG DNA promotes enhanced antitumor activity. Cancer Res. 64(16), 5850–5860 (2004).
  • He H, Genovese KJ, Nisbet DJ, Kogut MH. Synergy of CpG oligodeoxynucleotide and double-stranded RNA (poly I:C) on nitric oxide induction in chicken peripheral blood monocytes. Mol. Immunol. 44(12), 3234–3242 (2007).
  • Zhu Q, Egelston C, Gagnon S et al. 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(2), 607–616 (2010).
  • Cluff CW. Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines: clinical results. Adv. Exp. Med. Biol. 667, 111–123 (2009).
  • Kruit WH, Suciu S, Dreno B et al. 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(19), 2413–2420 (2013).
  • Hamilton E, Blackwell K, Hobeika AC et al. Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected]. J. Transl. Med. 10, 28–34 (2012).
  • Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV. CpG oligodeoxynucleotides act as adjuvants that switch on T helper (Th1) immunity. J. Exp. Med. 186, 1623–1631 (1997).
  • Davis HL, Weeranta R, Waldschmidt TJ, Tygrett L, Schorr J, Krieg AM. CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J. Immunol. 160, 870–876 (1998).
  • Brazolot Millan CL, Weeratna R, Krieg AM, Siegrist CA, Davis HL. 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 (1998).
  • Cooper CL, Davis HL, Morris ML et al. 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(6), 693–701 (2004).
  • Halperin SA, Van NG, Smith B, Abtahi S, Whiley H, Eiden JJ. 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(19–20), 2461–2467 (2003).
  • Rynkiewicz D, Rathkopf M, Sim I et al. Marked enhancement of the immune response to BioThrax(R) (Anthrax Vaccine Adsorbed) by the TLR9 agonist CPG 7909 in healthy volunteers. Vaccine 29(37), 6313–6320 (2011).
  • Cooper CL, Davis HL, Morris ML et al. Safety and immunogenicity of CPG 7909 injection as an adjuvant to Fluarix influenza vaccine. Vaccine 22(23–24), 3136–3143 (2004).
  • Speiser DE, Lienard D, Rufer N et al. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J. Clin. Invest 115(3), 739–746 (2005).
  • Ioannou XP, Griebel P, Hecker R, Babiuk LA, van Drunen Littel-van den Hurk. The immunogenicity and protective efficacy of bovine herpesvirus 1 glycoprotein D plus Emulsigen are increased by formulation with CpG oligodeoxynucleotides. J. Virol. 76(18), 9002–9010 (2002).
  • Ioannou XP, Gomis SM, Karvonen B, Hecker R, Babiuk LA, van Drunen Littel-van den Hurk. 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(1–2), 127–137 (2002).
  • Jones TR, Obaldia N, Gramzinski RA et al. Synthetic oligodeoxynucleotides containing CpG motifs enhance immunogenic vaccine in Aotus monkeys. Vaccine 17(23–24), 3065–3071 (1999).
  • Hirunpetcharat C, Wipasa J, Sakkhachornphop S et al. 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(21–22), 2923–2932 (2003).
  • Kumar S, Jones TR, Oakley MS et al. CpG oligodeoxynucleotide and Montanide ISA 51 adjuvant combination enhanced the protective efficacy of a subunit malaria vaccine. Infect. Immun. 72(2), 949–957 (2004).
  • Nashar TO, Amin T, Marcello A, Hirst TR. Current progress in the development of the B subunits of cholera toxin and escherichia coli heat-labile enterotoxin as carriers for the oral delivery of heterologous antigens and epitopes. Vaccine 11(2), 235–240 (1993).
  • Lycke N, Bemark M. Mucosal adjuvants and long-term memory development with special focus on CTA1-DD and other ADP-ribosylating toxins. Mucosal Immunol. 3(6), 556–566 (2010).
  • Sanchez J, Holmgren J. Cholera toxin – a foe & a friend. Indian J. Med. Res. 133, 153–163 (2011).
  • Holmgren J, Harandi AM, Czerkinsky C. Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA. Expert Rev. Vaccines 2(2), 205–217 (2003).
  • Skelding KA, Hickey DK, Horvat JC et al. Comparison of intranasal and transcutaneous immunization for induction of protective immunity against Chlamydia muridarum respiratory tract infection. Vaccine 24(3), 355–366 (2006).
  • Jiang W, Baker HJ, Smith BF. Mucosal immunization with helicobacter, CpG DNA, and cholera toxin is protective. Infect. Immun. 71(1), 40–46 (2003).
  • Nystrom-Asklin J, Adamsson J, Harandi AM. The adjuvant effect of CpG oligodeoxynucleotide linked to the non-toxic B subunit of cholera toxin for induction of immunity against H. pylori in mice. Scand. J. Immunol. 67(5), 431–440 (2008).
  • Norton EB, Clements JD, Voss TG, Cardenas-Freytag L. Prophylactic administration of bacterially derived immunomodulators improves the outcome of influenza virus infection in a murine model. J. Virol. 84(6), 2983–2995 (2010).
  • McCluskie MJ, Davis HL. 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 (1998).
  • Boyaka PN, Tafaro A, Fischer R, Leppla SH, Fujihashi K, McGhee JR. Effective mucosal immunity to anthrax: neutralizing antibodies and Th cell responses following nasal immunization with protective antigen. J. Immunol. 170(11), 5636–5643 (2003).
  • Bargieri DY, Rosa DS, Lasaro MA, Ferreira LC, Soares IS, Rodrigues MM. Adjuvant requirement for successful immunization with recombinant derivatives of Plasmodium vivax merozoite surface protein-1 delivered via the intranasal route. Mem. Inst. Oswaldo Cruz 102(3), 313–317 (2007).
  • Chandy AG, Nurkkala M, Josefsson A, Eriksson K. Therapeutic dendritic cell vaccination with Ag coupled to cholera toxin in combination with intratumoural CpG injection leads to complete tumour eradication in mice bearing HPV 16 expressing tumours. Vaccine 25(32), 6037–6046 (2007).
  • Giddings OK, Eickhoff CS, Sullivan NL, Hoft DF. Intranasal vaccinations with the trans-sialidase antigen plus CpG adjuvant induce mucosal immunity protective against conjunctival Trypanosoma cruzi challenges. Infect. Immun. 78(3), 1333–1338 (2010).
  • Tengvall S, Lundqvist A, Eisenberg RJ, Cohen GH, Harandi AM. 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(11), 5283–5291 (2006).
  • Kuan RK, Janssen R, Heyward W, Bennett S, Nordyke R. Cost-effectiveness of hepatitis B vaccination using HEPLISAV in selected adult populations compared to Engerix-B((R)) vaccine. Vaccine 31(37), 4024–4032 (2013).
  • Eng NF, Bhardwaj N, Mulligan R, Diaz-Mitoma F. The potential of 1018 ISS adjuvant in hepatitis B vaccines: HEPLISAV™ review. Hum. Vaccin. Immunother. 9(8), 1661–1672 (2013).
  • Cooper C, Mackie D. Hepatitis B surface antigen-1018 ISS adjuvant-containing vaccine: a review of HEPLISAV safety and efficacy. Expert. Rev. Vaccines 10(4), 417–427 (2011).
  • Klinman DM, Xie H, Little SF, Currie D, Ivins BE. CpG oligonucleotides improve the protective immune response induced by the anthrax vaccination of rhesus macaques. Vaccine 22(21–22), 2881–2886 (2004).
  • Klinman DM, Currie D, Lee G, Grippe V, Merkel T. Systemic but not mucosal immunity induced by AVA prevents inhalational anthrax. Microbes Infect. 9(12–13), 1478–1483 (2007).
  • xie H, Gursel I, Ivins BE et al. CpG oligodeoxynucleotides adsorbed onto polylactide-co-glycolide microparticles improve the immunogenicity and protective activity of the licensed anthrax vaccine. Infect. Immun. 73(2), 828–833 (2005).
  • Tross D, Klinman DM. Effect of CpG oligonucleotides on vaccine-induced B cell memory. J. Immunol. 181(8), 5785–5790 (2008).
  • Hopkins RJ, Daczkowski NF, Kaptur PE et al. 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(30), 3051–3058 (2013).
  • Rynkiewicz D, Rathkopf M, Sim I et al. Marked enhancement of the immune response to BioThrax(R) (Anthrax Vaccine Adsorbed) by the TLR9 agonist CPG 7909 in healthy volunteers. Vaccine 29(37), 6313–6320 (2011).
  • Ellis RD, Mullen GE, Pierce M et al. 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(31), 4104–4109 (2009).
  • Duncan CJ, Sheehy SH, Ewer KJ et al. Impact on malaria parasite multiplication rates in infected volunteers of the protein-in-adjuvant vaccine AMA1-C1/Alhydrogel+CPG 7909. PLoS ONE 6(7), e22271 (2011).
  • Ellis RD, Martin LB, Shaffer D et al. 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(1), e8787 (2010).
  • Sagara I, Ellis RD, Dicko A et al. 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(52), 7292–7298 (2009).
  • Mullen GE, Ellis RD, Miura K et al. Phase 1 trial of AMA1-C1/Alhydrogel plus CPG 7909: an asexual blood-stage vaccine for Plasmodium falciparum malaria. PLoS ONE 3(8), e2940 (2008).
  • Tighe H, Takabayashi K, Schwartz D et al. 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 (2000).
  • Creticos PS, Schroeder JT, Hamilton RG et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N. Engl. J. Med. 355(14), 1445–1455 (2006).
  • Simons FE, Shikishima Y, Van NG, Eiden JJ, HayGlass KT. Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J. Allergy Clin. Immunol. 113(6), 1144–1151 (2004).
  • Senti G, Johansen P, Haug S et al. 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(4), 562–570 (2009).
  • Klimek L, Willers J, Hammann-Haenni A et al. Assessment of clinical efficacy of CYT003-QbG10 in patients with allergic rhinoconjunctivitis: a phase IIb study. Clin. Exp. Allergy 41(9), 1305–1312 (2011).
  • Bioley G, Guillaume P, Luescher I et al. 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(2), 161–168 (2009).
  • Valmori D, Souleimanian NE, Tosello V et al. 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. USA 104(21), 8947–8952 (2007).
  • Fourcade J, Kudela P, Andrade Filho PA et al. Immunization with analog peptide in combination with CpG and montanide expands tumor antigen-specific CD8+ T cells in melanoma patients. J. Immunother. 31(8), 781–791 (2008).
  • van Ojik H, Kruit W, Portielje J et al. Phase I/II study with CPG 7909 as adjuvant to vaccination with MAGE-3 protein in patients with MAGE-3 positive tumors. Ann. Oncol. 13( Suppl.), 157–158 Abstract O579 (2002).
  • Haining WN, Davies J, Kanzler H et al. CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans. Clin. Cancer Res. 14(17), 5626–5634 (2008).
  • Goldinger SM, Dummer R, Baumgaertner P et al. 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(11), 3049–3061 (2012).
  • Carson WE, III, Shapiro CL, Crespin TR, Thornton LM, Andersen BL. Cellular immunity in breast cancer patients completing taxane treatment. Clin. Cancer Res. 10(10), 3401–3409 (2004).
  • Lake RA, Robinson BW. Immunotherapy and chemotherapy--a practical partnership. Nat. Rev. Cancer 5(5), 397–405 (2005).
  • Carpentier A, Laigle-Donadey F, Zohar S et al. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro. Oncol. 8(1), 60–66 (2006).
  • Kim YH, Gratzinger D, Harrison C et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 119(2), 355–363 (2012).
  • Manegold C, Gravenor D, Woytowitz D et al. 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(24), 3979–3986 (2008).
  • Friedberg JW, Kim H, McCauley M et al. 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(2), 489–495 (2005).
  • Leonard JP, Link BK, Emmanouilides C et al. 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(20), 6168–6174 (2007).
  • Brody JD, Ai WZ, Czerwinski DK et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J. Clin. Oncol. 28(28), 4324–4332 (2010).
  • Hofmann MA, Kors C, Audring H, Walden P, Sterry W, Trefzer U. Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma. J. Immunother. 31(5), 520–527 (2008).
  • Molenkamp BG, Sluijter BJ, Van Leeuwen PA et al. Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients. Clin. Cancer Res. 14(14), 4532–4542 (2008).
  • Vasievich EA , Huang L. The suppressive tumor microenvironment: a challenge in cancer immunotherapy. Mol. Pharm. 8(3), 635–641 (2011).
  • Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182(8), 4499–4506 (2009).
  • Shirota Y, Shirota H, Klinman DM. Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells. J. Immunol. 188(4), 1592–1599 (2012).
  • Zoglmeier C, Bauer H, Norenberg D et al. CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice. Clin. Cancer Res. 17(7), 1765–1775 (2011).
  • Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov. 5(6), 471–484 (2006).
  • Krieg AM, Efler SM, Wittpoth M, Al Adhami MJ, Davis HL. 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(6), 460–471 (2004).
  • Link BK, Ballas ZK, Weisdorf D et al. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J. Immunother. 29(5), 558–568 (2006).
  • Le HC, Cohen P, Bousser MG, Letellier P, Guillevin L. Suspected hepatitis B vaccination related vasculitis. J. Rheumatol. 26(1), 191–194 (1999).
  • Allen MB, Cockwell P, Page RL. Pulmonary and cutaneous vasculitis following hepatitis B vaccination. Thorax 48(5), 580–581 (1993).
  • Gilkeson GS, Riuz P, Howell D, Lefkowith JB, Pisetsky DS. Induction of immune-mediated glomerulonephritis in normal mice immunized with bacterial DNA. Clin. Immunol. Immunopathol. 68, 283–292 (1993).
  • Steinberg AD, Krieg AM, Gourley MF, Klinman DM. Theoretical and experimental approaches to generalized autoimmunity. Immunol. Rev. 118, 129–163 (1990).
  • Gilkeson GS, Pippen AM, Pisetsky DS. Induction of cross-reactive anti-dsDNA antibodies in preautoimmune NZB/NZW mice by immunization with bacterial DNA. J. Clin. Invest. 95, 1398–1402 (1995).
  • Yi A-K, Hornbeck P, Lafrenz DE, Krieg AM. 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-xl. J. Immunol. 157, 4918–4925 (1996).
  • Krieg AM, Vollmer J. Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol. Rev. 220, 251–269 (2007).
  • Yu P, Musette P, Peng SL. Toll-like receptor 9 in murine lupus: more friend than foe! Immunobiology 213(2), 151–157 (2008).
  • Gilkeson GS, Conover JS, Halpern M, Pisetsky DS, Feagin A, Klinman DM. Effects of bacterial DNA on cytokine production by (NZB/NZW)F1 mice. J. Immunol. 161, 3890–3895 (1998).
  • Mor G, Singla M, Steinberg AD, Hoffman SL, Okuda K, Klinman DM. Do DNA vaccines induce autoimmune disease? Hum. Gene Ther. 8, 293–300 (1997).
  • Karbach J, Neumann A, Wahle C, Brand K, Gnjatic S, Jager E. Therapeutic administration of a synthetic CpG oligodeoxynucleotide triggers formation of anti-CpG antibodies. Cancer Res. 72(17), 4304–4310 (2012).
  • DeFrancesco L. Dynavax trial halted. Nat. Biotechnol. 26(5), 484 (2008).
  • Krieg AM, Yi A, Matson S et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–548 (1995).
  • Jaafari MR, Badiee A, Khamesipour A et al. The role of CpG ODN in enhancement of immune response and protection in BALB/c mice immunized with recombinant major surface glycoprotein of Leishmania (rgp63) encapsulated in cationic liposome. Vaccine 25(32), 6107–6117 (2007).
  • Oussoren C, Storm G. Liposomes to target the lymphatics by subutaneous administration. Adv. Drug Deliv. Rev. 50(1–2), 143–156 (2001).
  • Li WM, Dragowska WH, Bally MB, Schutze-Redelmeier MP. Effective induction of CD8+ T-cell response using CpG oligodeoxynucleotides and HER-2/neu-derived peptide co-encapsulated in liposomes. Vaccine 21(23), 3319–3329 (2003).
  • Jiao X, Wang RY, Qiu Q, Alter HJ, Shih JW. Enhanced hepatitis C virus NS3 specific Th1 immune responses induced by co-delivery of protein antigen and CpG with cationic liposomes. J. Gen. Virol. 85(Pt 6), 1545–1553 (2004).
  • Whitmore MM, Li S, Falo L Jr, Huang L. Systemic administration of LPD prepared with CpG oligonucleotides inhibits the growth of established pulmonary metastases by stimulating innate and acquired antitumor immune responses. Cancer Immunol. Immunother. 50(10), 503–514 (2001).
  • Salem AK, Searson PC, Leong KW. Multifunctional nanorods for gene delivery. Nat. Mater. 2(10), 668–671 (2003).
  • Tafaghodi M, Sajadi Tabassi SA, Jaafari MR. Induction of systemic and mucosal immune responses by intranasal administration of alginate microspheres encapsulated with tetanus toxoid and CpG-ODN. Int. J. Pharm. 319(1–2), 37–43 (2006).
  • Borges O, Cordeiro-da-Silva A, Tavares J et al. Immune response by nasal delivery of hepatitis B surface antigen and codelivery of a CpG ODN in alginate coated chitosan nanoparticles. Eur. J. Pharm. Biopharm. 69(2), 405–416 (2008).
  • Demoulins T, Bassi I, Thomann-Harwood L et al. Alginate-coated chitosan nanogel capacity to modulate the effect of TLR ligands on blood dendritic cells. Nanomedicine 9(6), 806–817 (2013).
  • Gursel I, Gursel M, Ishii KJ, Klinman DM. Sterically stabilized cationic liposomes improve the uptake and immunostimulatory activity of CpG oligonucleotides. J. Immunol. 167(6), 3324–3328 (2001).
  • Singh M, Ugozzoli M, Briones M, Kazzaz J, Soenawan E, O’Hagan DT. The effect of CTAB concentration in cationic PLG microparticles on DNA adsorption and in vivo performance. Pharm. Res. 20(2), 247–251 (2003).
  • Tafaghodi M, Khamesipour A, Jaafari MR. Immunization against leishmaniasis by PLGA nanospheres encapsulated with autoclaved Leishmania major (ALM) and CpG-ODN. Parasitol. Res. 108(5), 1265–1273 (2011).
  • Diwan M, Tafaghodi M, Samuel J. Enhancement of immune responses by co-delivery of a CpG oligodeoxynucleotide and tetanus toxoid in biodegradable nanospheres. J. Control. Release 85(1–3), 247–262 (2002).
  • Lv S, Wang J, Dou S et al. Nanoparticles encapsulating HBV-CpG induce therapeutic immunity against hepatitis B virus infection. Hepatology doi:10.1002/hep.26654 (2013) ( Epub ahead of print).
  • Nikitczuk KP, Schloss RS, Yarmush ML, Lattime EC. PLGA-polymer encapsulating tumor antigen and CpG DNA administered into the tumor microenvironment elicits a systemic antigen-specific IFN-gamma response and enhances survival. J. Cancer Ther. 4(1), 280–290 (2013).
  • Beeh KM, Kanniess F, Wagner F et al. The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma. J. Allergy Clin. Immunol. 131(3), 866–874 (2013).
  • Karbach J, Neumann A, Atmaca A et al. Efficient in vivo priming by vaccination with recombinant NY-ESO-1 protein and CpG in antigen naive prostate cancer patients. Clin. Cancer Res. 17(4), 861–870 (2011).
  • Cluff CW. Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines: clinical results. Adv. Exp. Med. Biol. 667, 111–123 (2010)
  • Hirsh V, Paz-Ares L, Boyer M et al. Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J. Clin. Oncol. 29(19), 2667–2674 (2011).
  • Manegold C, van ZN, Szczesna A et al. A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann. Oncol. 23(1), 72–77 (2012).

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