Abstract
Oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG ODN) act as potent Th1-like immune enhancers with many antigens in animal models. We have extended these observations to the first clinical evaluation of the safety, tolerability and immunogenicity of CPG 7909 when added to a commercial HBV vaccine. In a randomized, double-blind phase I dose escalation study, healthy volunteers aged 18–35 years were vaccinated at 0, 4 and 24 weeks by intramuscular injection with Engerix-B® (GlaxoSmithKline). The regular adult dose of 20 μg recombinant hepatitis B surface antigen (HBsAg) adsorbed to alum was administered mixed with saline (control) or with CPG 7909 at one of three doses (0.125, 0.5 or 1.0 mg). HBsAg-specific antibody responses (anti-HBs) appeared significantly sooner and were significantly higher at all timepoints up to and including 24 weeks in CPG 7909 recipients compared to control subjects (p⩽0.001). Strikingly, most CpG 7909-vaccinated subjects developed protective levels of anti-HBs IgG within just two weeks of the priming vaccine dose. A trend towards higher rates of positive cytotoxic T cell lymphocyte responses was noted in the two higher dose groups of CPG 7909 compared to controls. The most frequently reported adverse events were injection site reactions, flu-like symptoms and headache. While these were more frequent in CPG 7909 groups than in the control group (p<0.0001), most were reported to be of mild to moderate intensity regardless of group. In summary, CPG 7909 as an adjuvant to Engerix-B was well-tolerated and enhanced vaccine immunogenicity. CPG 7909 may allow the development of a two-dose prophylactic HBV vaccine.
Similar content being viewed by others
References
Lee WM: Hepatitis B virus infection. N Engl J Med337:1733–1745, 1997
Maddrey WC: Hepatitis B: An important public health issue. J Med Virol61:362–366, 2000
Hepatitis B Vaccination–United States, 1982–2002, MMWR Morb Mortal Wkly Rep51:549–552, 563, 2002
Chisari FV: Cytotoxic T cells and viral hepatitis. J Clin Invest99:1472–1477, 1997
Rehermann B: Intrahepatic T cells in hepatitis B: Viral control versus liver cell injury. J Exp Med191:1263–1268, 2000
Krieg AM: CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol20:709–760, 2002
Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV: CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J Exp Med186:1623–1631, 1997
Lipford GB, Bauer M, Blank C, Reiter R, Wagner H, Heeg K: CpG-containing synthetic oligonucleotides promote B and cytotoxic T cell responses to protein antigen: A new class of vaccine adjuvants. Eur J Immunol27:2340–2344, 1997
Roman M, Martin-Orozco E, Goodman JS, Nguyen MD, Sato Y, Ronaghy A, Kornbluth RS, Richman DD, Carson DA, Raz E: Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nat Med3:849–854, 1997
Krieg AM, Davis HL: Enhancing vaccines with immune stimulatory CpG DNA. Curr Opin Mol Ther3:15–24, 2001
Vollmer J, Weeratna R, Payette P, Jurk M, Schetter C, Laucht M, Wader T, Tluk S, Liu M, Davis HL, Krieg AM: Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur J Immunol34:251–262, 2004
Davis HL, Weeratna R, Waldschmidt TJ, Tygrett L, Schorr J, Krieg AM, Weeranta R: CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J Immunol160:870–876, 1998
Weeratna R, Comanita L, Davis HL: CPG ODN allows lower dose of antigen against hepatitis B surface antigen in BALBc mice. Immunol Cell Biol81:59–62, 2003
Weeratna RD, Brazolot Millan CL, McCluskie MJ, Siegrist CA, Davis HL: Priming of immune responses to hepatitis B surface antigen in young mice immunized in the presence of maternally derived antibodies. FEMS Immunol Med Microbiol30:241–247, 2001
Weeratna RD, McCluskie MJ, Xu Y, Davis HL: CpG DNA induces stronger immune responses with less toxicity than other adjuvants. Vaccine18:1755–1762, 2000
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 Immunol161:4463–4466, 1998
Davis HL, Suparto II, Weeratna RR, Jumintarto Iskandriati DD, Chamzah SS, Ma’ruf AA, Nente CC, Pawitri DD, Krieg AM, Heriyanto Smits W, Sajuthi DD: CpG DNA overcomes hyporesponsiveness to hepatitis B vaccine in orangutans. Vaccine18:1920–1924, 2000
Hartmann G, Weeratna RD, Ballas ZK, Payette P, Blackwell S, Suparto I, Rasmussen WL, Waldschmidt M, Sajuthi D, Purcell RH, Davis HL, Krieg AM: Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol164:1617–1624, 2000
Halperin SA, van Nest G, 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. Vaccine21:2461–2467, 2003
Ambrosch F, Wiedermann G, Kundi M, Leroux-Roels G, Desombere I, Garcon N, Thiriart C, Slaoui M, Thoelen S: A hepatitis B vaccine formulated with a novel adjuvant system. Vaccine 18:2095–2101, 2000
Thoelen S, van Damme P, Mathei C, Leroux-Roels G, Desombere I, Safary A, Vandepapeliere P, Slaoui M, Meheus A: Safety and immunogenicity of a hepatitis B vaccine formulated with a novel adjuvant system. Vaccine16:708–714, 1998
Galbraith WM, Hobson WC, Giclas PC, Schechter PJ, Agrawal S: Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res Dev 4:201–206, 1994
West DJ: Clinical experience with hepatitis B vaccines. Am J Infect Control17:172–180, 1989
Hasan MS, Agosti JM, Reynolds KK, Tanzman E, Treanor JJ, Evans TG: Granulocyte macrophage colony-stimulating factor as an adjuvant for hepatitis B vaccination of healthy adults. J Infect Dis 180:2023–2026, 1999
Evans TG, Hasan M, Galibert L, Caron D: The use of Flt3 ligand as an adjuvant for hepatitis B vaccination of healthy adults. Vaccine21:322–329, 2002
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
COOPER, C., DAVIS, H., MORRIS, M. 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, 693–701 (2004). https://doi.org/10.1007/s10875-004-6244-3
Issue Date:
DOI: https://doi.org/10.1007/s10875-004-6244-3