Persistent hepatitis B virus (HBV) infection represents a major public health concern because of its association with chronic liver disease and the propensity of the disease to progress to cirrhosis and hepatocellular carcinoma. Despite the availability of a prophylactic vaccine effective in a majority of the population, alternative vaccination strategies are being sought to induce protective responses in healthy non-responders and to boost and broaden T cell responses in chronically infected patients, which may lead to a better control of the virus and/or its eventual complete clearance. In this issue of the European Journal of Immunology immunization of BALB/c mice intramuscularly with a DNA vaccine encoding the hepatitis virus B surface antigen (HBsAg) was shown to result in prolonged secretion of HBsAg into the serum and the elicitation of HBsAg-specific antibodies. In fact, the vaccine was so efficient that the antibodies and HBsAg formed circulating immune complexes and induced kidney and liver lesions similar to those observed in chronically infected patients. This commentary discusses these results in terms of the safety of plasmid DNA-vectored genetic vaccines in general, the use of DNA vaccines expressing HBsAg for the treatment of chronic hepatitis and the consequences of prolonged immunogen expression for the development of protective immune responses.