Immunization represents the most effective approach to the prevention of hepatitis B virus infection and the long-term complications of chronic disease, including liver cancer and liver failure. Current vaccines require three doses to achieve maximal immunogenicity and fail to produce long-lasting protection in 5-10% of immune-competent individuals and in a much larger proportion of immune-compromised patients. Immunostimulatory DNA sequence (ISS) vaccine adjuvants, when combined with vaccine antigens, may increase immunogenicity and reduce the number of required doses to achieve this goal. 1018 ISS plus recombinant hepatitis B surface antigen has been demonstrated to achieve these goals in immune competent and vaccine-hyporesponsive populations without compromising recipient safety.