a viral antigen under the control of a eukaryotic promoter an immune response to the viral antigen could be achieved [1]. Basically, the plasmid should be taken up by the cells, transported to the nucleus, start transcription and translation of the viral antigen. The antigen is then presented in both the major histocompatibility complex class I-and IIpathways, presumably by the transport of the antigen, and/ or transfected cell, by dendritic cells to a nearby lymph node. The lymph node is most likely the key site for the priming of T cells to the vaccine antigen, albeit the role for the transfected cell in antigen presentation has not been fully elucidated. The DNA vaccine technology was advanced to human testing where it became painfully obvious that DNA vaccines did not work as well in humans as they did in small animals [2][3][4]. Why was that? One factor is certainly the poor uptake of the DNA when simply injected in the muscle or in the skin. This started an era of trying to improve the delivery of DNA vaccines to larger animals.
In vivo electroporation (EP) or electrotransfer (ET)The concept of applying a current over cell membranes has been used since the 1970s for introducing various compounds and substances to cells [5,6]. The strong but transient electrical pulses either introduce transient pores in the cell membrane or destabilize the cell membrane whereby extra-cellular compounds can enter the cell. Thus, one can argue whether EP or ET is the best term to use.The technology was later transferred to the in vivo situation when it was noted that anticancer drugs were poorly taken up by cells in vivo [7]. Hence, by either injecting the anticancer drug into the tumor or administering the anticancer drug systemically, and then applying transient electrical Abstract DNA vaccination has historically failed to raise strong immune responses in humans. Recent delivery techniques such as the gene gun and in vivo electroporation (EP)/electrotransfer (ET) have completely changed the efficiency of DNA vaccines in humans. In vivo EP exerts multiple effects that contribute to its efficiency. The two central factors are most likely the increased DNA uptake due to the transient membrane destabilization, and the local tissue damage acting as an adjuvant. To date, several studies in humans have used in vivo EP/ET to deliver DNA. Some of these results have been quite promising with strong T cell responses and/or transient effects on the viral replication. This suggests that improved strategies of in vivo EP/ET can be a future way to deliver DNA in humans.Keywords Therapeutic vaccine · HBV · DNA vaccine · Electroporation · T cell DNA vaccines DNA vaccines were first described in the early 1990s. It was shown that by simply injecting a plasmid, expressing This article is part of the special issue "Therapeutic vaccination in chronic hepatitis B-approaches, problems, and new perspectives."