title: A review of the role of CpG oligodeoxynucleotides as toll-like receptor 9 agonists in prophylactic and therapeutic vaccine development in infectious diseases.
abstract: This article reviews the biology of Toll-like receptors, the current understanding of the mechanism by which CpG oligodeoxynucleotides (ODNs) perturb immune function and the published literature describing their evaluation in the development of vaccines in humans. The role of these molecules as immune modulators in HCV treatment is also considered. There has been considerable research evaluating the role of CpG ODNs as an adjuvant and immune modulator in hepatitis B, hepatitis C and influenza. The safety and immunogenicity of the 1018 ISS compound in combination with Engerix-B was assessed in 99 healthy, adult seronegative volunteers. One month following the first immunization dose, 78.7% in the rHBsAg plus 1018 ISS group versus 11.8% in the Engerix-B group achieved protective titres. One hundred percent of rHBsAg plus 1018 ISS and 18.0% of hepatitis B vaccine-alone recipients were seroprotected 1 week following the second dose of study vaccine. After all doses of vaccine had been administered, seroprotection rates were 100% and 64%, respectively (p < 0.001). CPG 7909 was co-administered with Engerix-B in 56 healthy adults. After the second injection (week 6 time point), seroprotection was achieved in 100% of CPG 7909 recipients (0.5 mg 13/13; 1.0 mg 12/12; 0.125 mg 12/12) compared with 55% (6/11) of control participants (p = 0.0003). Twelve months post prime, all subjects who had received the full course of vaccination maintained seroprotective anti-HBs titres. The safety and immunogenicity of Engerix B plus CPG 7909 was assessed in HIV seropositive patients. All CPG 7909 recipients (n = 19) and 17/19 (89%) control subjects achieved seroprotection by 2 weeks after the third and final injection (10 weeks). Seroprotective titres remained in all CPG 7909 recipients at 48 weeks (100%) versus 12/19 (63%) for controls (p = 0.008). This cohort of HIV-infected patients was followed at 6-month intervals for up to 60 months after enrolment. The difference in seroprotection (> or =10 mIU/L) and GMT between study arms remained significant (p < 0.05) at all time points from month 24 to month 60. There is great potential for CpG ODN as vaccine adjuvants and as therapeutic immune modulators. The use of these molecules as a hepatitis B vaccine adjuvant is most promising.
authors.affiliation: Division of Infectious Diseases, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Kaveri
authors.initials: K
authors.lastname: Gupta
authors.forename: Curtis
authors.initials: C
authors.lastname: Cooper
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D015195:Drug Design; D006509:Hepatitis B / Q000276:immunology / Q000517:prevention & control; D006526:Hepatitis C / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control; D008288:Malaria / Q000276:immunology / Q000517:prevention & control; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D014612:Vaccines / Q000276:immunology*
chemical_list: C408982:CPG-oligonucleotide; D007155:Immunologic Factors; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D014612:Vaccines