According to UNAIDS, there were a total of 36.7 million people living with HIV and 2.1 million new infections in 2015. Eastern and Southern Africa continues to be most severely affected, accounting for 51.7% of the total global infections. Antiretroviral therapy has contributed to slowing the HIV epidemic. However, the low coverage and strict treatment adherence requirement remain significant challenges.1,2 Pre- and postexposure prophylaxes have been used to prevent HIV infection.3,4 Yet, the effectiveness of pre-exposure prophylaxis in high-incidence heterosexual populations has been poorly achieved and is again highly dependent on drug adherence.5 Although a vaginal microbicide containing tenofovir reduced HIV acquisition by 39%,6 a risk for low treatment adherence was demonstrated by the VOICE trial,7 compromising the protective effect previously reported. Therefore, a safe and effective prophylactic HIV vaccine remains the best long-term solution for controlling the HIV pandemic. After 30 years of research, there have been over 200 phase I to phase III clinical HIV vaccine trials of different vaccine candidates,8,9 but only one of the six HIV vaccine efficacy trials, the RV144 study, has demonstrated a modest efficacy (31.2%) against HIV acquisition at 42 months.10 The analysis of immune correlates of the RV144 trial revealed that IgG antibodies against the V1/V2 region of HIV-1 Envelope (Env) were inversely correlated with the risk of HIV infection, while the presence of IgA Env-binding antibodies was directly correlated with risk of infection.11–13 In addition, antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies and antibodies to the V3 region correlated with reduced risk of HIV infection in vaccinees with low IgA Env binding antibody titers.14 Analysis of the T cell responses confirmed HIV gp120 V2 specificity and revealed CD4+ T cells exhibiting polyfunctionality and cytolytic capacity.15 Contrary to other infectious disease vaccines where the development of neutralizing antibodies (NAbs) plays a central role in immunity, protection from HIV may require both functional antibody- and cell-mediated immune responses.8 Previous studies conducted in Sweden16,17 and Tanzania18 assessed the safety and immunogenicity of a multigene multiclade HIV-1 DNA vaccine candidate (HIV-DNA) boosted with heterologous HIV-1 modified vaccinia virus AnkaraChiang Mai double recombinant vaccine (HIV-MVA). These trials explored different modes of delivery, the use of needlefree administration and dosing of the HIV-DNA vaccine, and demonstrated that intradermal (ID) priming using a needlefree device for HIV-DNA delivery (Bioject) elicited higher FN-c ELISpot responses to Env when compared to the intramuscular (IM) route of delivery, and the majority of subjects developed HIV-specific antibodies after two HIV-MVA vaccinations.18 However, five injections with two pools of HIV-DNA plasmids at separate sites were required to achieve the desired 1,000 lg dose of HIV-DNA in a maximum injectable volume of 0.1 ml, using the Bioject. Munseri et al. showed that HIV-DNA ID priming could be simplified, and two injections of a total of 600 lg administered as combined plasmid pools primed cellular immune responses as efficiently as the standard regimen...