Although there has been a decline in the number of new human immunodeficiency virus (HIV) infections over the years, millions of people continue to be exposed and infected [1]. More than 200 HIV vaccine phase I and II, and 6 efficacy trials have been conducted [2, 3]. The RV144 Thai trial is the only trial to show a moderate protective effect using a canary poxvirus vector (ALVAC-HIV vcp1521)-based prime followed by alum-adjuvanted protein (AIDSVAX-gp120 B/E) boost vaccination strategy [4]. In the analysis of immune correlates of risk of HIV infection, antibodies against the V1/V2 region of HIV-1 envelope (Env) were inversely correlated with the rate of HIV-infection, while the presence of IgA Env-binding antibodies was associated with a lack of protection. Furthermore, antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies correlated with a reduced risk of HIV-infection in vaccinees with low IgA Env binding antibody titers [5]. DNA-based vaccines carrying HIV-1 genes have been shown to be safe and to induce potent cellular immune responses when used in combination with genetically modified vector-based vaccines containing HIV-1 inserts [6–13]. Over the past 11 years, the safety and immunogenicity of a multigene multiclade HIV-1 DNA vaccine candidate (HIV-DNA), boosted with heterologous HIV-1 modified vaccinia virus Ankara (MVA)-Chiang Mai double recombinant (CMDR) vaccine (HIV-MVA) have been assessed in phase I/II HIV vaccine trials [11–16]. Different doses and modes of delivering HIV-DNA vaccine were evaluated in these trials. Potent and durable immune responses were induced after three HIV-DNA and two HIV-MVA immunizations [11, 17, 18]. Furthermore, HIV-DNA vaccine administered intradermally (ID) in a simplified injection regimen (one or two injections), using a needle-free jet device (Biojector) in a total dose of 600μg efficiently primed cellular immune responses after HIV-MVA vaccination [12]. Electroporation (EP) has been used both in pre-clinical and clinical studies to augment the plasmid DNA immunogenicity [19, 20]. EP increases the transfection efficiency into antigenpresenting cells (APCs) by creating transient pores in the cell membranes increasing the uptake of DNA. Clinical studies have suggested that intramuscular (IM) EP can enhance the immunogenicity of DNA vaccines [21, 22], but other routes of administration should be considered to reduce discomfort. Adjuvanted HIV-1 Env protein-based vaccines have been shown to stimulate humoral immune responses including binding and neutralizing antibodies [23]. Vax003 and Vax004 phase III trials, which evaluated vaccine regimens containing recombinant gp120 (B/E) and gp120 (B/B), respectively, failed to confer protection [24, 25]. In contrast, the RV144 trial which used a vectored-based prime vaccine and recombinant gp120 (B/E) protein boosts succeeded in conferring a moderate protection against HIV infection [4]. The present study builds on previous data from trials in Sweden, Tanzania and Mozambique [13, 14, 26], and...