Adults 40 years of age and older have been shown to be hypo-responsive immunologically to the currently available hepatitis B virus (HBV) vaccines. Three intramuscular doses of a Toll-like receptor 9 agonist, 1018 immunostimulatory sequence (1018 ISS) adjuvant, combined with recombinant hepatitis B surface antigen (HBsAg) demonstrated faster, superior, and more durable seroprotection than three doses of a licensed comparator HBV vaccine (Engerix-B(®)). This investigational vaccine, HBsAg-1018 ISS, was well tolerated with a safety profile similar to the comparator vaccine. These results suggest that HBsAg-1018 may be more effective in this hypo-responsive population.