A phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant.
Certain oligodeoxynuclotides with CpG motifs provide enhanced immune response to co-delivered antigens. We performed a phase I, observer-blinded, randomized study in healthy anti-hepatitis B surface antigen (anti-HBsAg) antibody negative adults to explore safety and immunogenicity of co-injection of recombinant HBsAg combined with an immunostimulatory DNA sequence (ISS) 1018 ISS. Four ISS dosage groups (N=12 per group) were used: 300, 650, 1000 or 3000 microg. For each group, two controls received 20 microg HBsAg alone, two controls received ISS alone, and eight subjects received ISS+20 microg HBsAg. Subjects received two doses 8 weeks apart. Injection site reactions (tenderness and pain on limb movement) were more frequent at higher ISS+HBsAg doses but were mainly mild and of short duration. Higher anti-HBsAg antibody levels were associated with higher ISS doses. Four weeks after the first dose, a seroprotective titer (>or=10 mIU/ml) was noted for 0, 25, 75, and 87.5% of subjects by increasing ISS dose group (P<0.05) for those who received ISS+HBsAg; 1 month after the second dose this increased to 62.5, 100, 100, and 100%, respectively. Geometric mean anti-HBsAg antibody levels by increasing ISS+HBsAg dose were 1.22, 5.78, 24.75, and 206.5 mIU/ml after the first dose and 65.37, 877.6, 1545, and 3045 mIU/ml after the second dose. We conclude that 1018 ISS+HBsAg was well tolerated and immunogenic in this phase I study in healthy adults and may offer the potential for enhancement of hepatitis B virus (HBV) immunization and protection after one or two doses or in individuals who fail to respond to the standard vaccine regimen.
Department of Pediatrics, Clinical Trials Research Center, Dalhousie University, IWK Health Centre, 5850 University Avenue, Halifax, NS, Canada B3J 3G9. shalperin@iwkgrace.ns.ca
Scott A
SA
Halperin
Gary
G
Van Nest
Bruce
B
Smith
Simin
S
Abtahi
Heather
H
Whiley
Joseph J
JJ
Eiden
D000276:Adjuvants, Immunologic / Q000009:adverse effects*; D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D006261:Headache / Q000139:chemically induced; D006514:Hepatitis B Surface Antigens / Q000009:adverse effects / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000009:adverse effects* / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D010146:Pain / Q000139:chemically induced; D018579:Patient Selection; D013873:Thionucleotides / Q000009:adverse effects / Q000276:immunology; D013997:Time Factors; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D013873:Thionucleotides; D014614:Vaccines, Synthetic