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Background DNA plasmids promise a pragmatic alternative to viral vectors for prime-boost HIV-1 vaccines. We evaluated DNA plasmid versus canarypox virus (ALVAC) primes in 2 randomized, double-blind, placebo-controlled trials in southern Africa with harmonized trial designs. HIV Vaccine Trials Network (HVTN) 111 tested DNA plasmid prime by needle or needleless injection device (Biojector) and DNA plasmid plus gp120 protein plus MF59 adjuvant boost. HVTN 100 tested ALVAC prime and ALVAC plus gp120 protein plus MF59 adjuvant boost (same protein/adjuvant as HVTN 111) by needle. Methods and findings The primary endpoints for this analysis were binding antibody (bAb) responses to HIV antigens (gp120 from strains ZM96, 1086, and TV1; variable 1 and 2 [V1V2] regions of gp120 from strains TV1, 1086, and B.CaseA, as 1086 V1V2 and B.CaseA were correlates of risk in the RV144 efficacy trial), neutralizing antibody (nAb) responses to pseudoviruses TV1c8.2 and MW925.26, and cellular responses to vaccine-matched antigens (envelope [Env] from strains ZM96, 1086, and TV1; and Gag from strains LAI and ZM96) at month 6.5, two weeks after the fourth vaccination. Per-protocol cohorts included vaccine recipients from HVTN 100 (n = 186, 60% male, median age 23 years) enrolled between February 9, 2015, and May 26, 2015 and from HVTN 111 (n = 56, 48% male, median age 24 years) enrolled between June 21, 2016, and July 13, 2017. IgG bAb response rates were 100% to 3 Env gp120 antigens in both trials. Response rates to V1V2 were lower and similar in both trials except to vaccine-matched 1086 V1V2, with rates significantly higher for the DNA-primed regimen than the ALVAC-primed regimen: 96.6% versus 72.7% (difference = 23.9%, 95% CI 15.6%–32.2%, p < 0.001). Among positive responders, bAb net mean fluorescence intensity (MFI) was significantly higher with the DNA-primed regimen than ALVAC-primed for 1086 V1V2 (geometric mean [GM] 2,833.3 versus 1,200.9; ratio = 2.36, 95% CI 1.42–3.92, p < 0.001) and B.CaseA V1V2 (GM 2314.0 versus 744.6, ratio = 3.11, 95% CI 1.51–6.38, p = 0.002). nAb response rates were >98% in both trials, with significantly higher 50% inhibitory dilution (ID50) among DNA-primed positive responders (n = 53) versus ALVAC-primed (n = 182) to tier 1A MW965.26 (GM 577.7 versus 265.7, ratio = 2.17, 95% CI 1.67–2.83, p < 0.001) and to TV1c8.2 (GM 187.3 versus 100.4, ratio = 1.87, 95% CI 1.48–2.35, p < 0.001). CD4+ T-cell response rates were significantly higher with DNA plasmid prime via Biojector than ALVAC prime (91.4% versus 52.8%, difference = 38.6%, 95% CI 20.5%–56.6%, p < 0.001 for ZM96.C; 88.0% versus 43.1%, difference = 44.9%, 95% CI 26.7%–63.1%, p < 0.001 for 1086.C; 55.5% versus 2.2%, difference = 53.3%, 95% CI 23.9%–82.7%, p < 0.001 for Gag LAI/ZM96). The study’s main limitations include the nonrandomized comparison of vaccines from 2 different trials, the lack of data on immune responses to other non–vaccine-matched antigens, and the uncertain clinical significance of the observed immunological effects. Conclusions In this study, we found that further investigation of DNA/protein regimens is warranted given enhanced immunogenicity to the V1V2 correlates of decreased HIV-1 acquisition risk identified in RV144, the only HIV vaccine trial to date to show any efficacy., Zoe Moodie and co-workers study immunological responses with DNA priming in trials of a candidate HIV vaccine., Author summary Why was this study done? HIV remains a major global health problem, especially in sub-Saharan Africa. Developing an efficacious HIV vaccine for subtype C infections, which predominate in southern Africa, is a high priority. Comparing immune responses after DNA plasmid versus viral vector priming in 2 similar subtype C HIV vaccine regimens could help inform the choice of priming strategy to use moving forward. DNA plasmid vaccines are cost-effective, easy to manufacture, and tolerable. What did the researchers do and find? We compared antibody and cellular immune responses to two phase I/II HIV-1 vaccines that differed in their priming mechanism (canarypox virus [ALVAC] vector versus DNA) but were matched in their protein boost and adjuvant. Specifically, we measured T-cell and binding and neutralizing antibody (nAb) responses to the vaccine-matched antigens from the HIV Vaccine Trials Network (HVTN) 100 and HVTN 111 trials. The vaccine regimens with DNA plasmid priming in general stimulated higher binding antibody (bAb) response magnitudes to the variable 1 and 2 (V1V2) correlates of decreased risk in RV144 and higher neutralizing responses to tier 1 viruses than the vaccine regimen with ALVAC priming. Both regimens stimulated high binding and neutralizing response rates, while DNA plasmid priming with MF59 adjuvanted protein boost induced significantly higher CD4+ T-cell response rates than ALVAC priming with MF59 adjuvanted protein boost. What do these findings mean? Our results suggest that DNA plasmid is a superior priming method for stimulating vaccine-matched humoral and cellular responses for HIV vaccine trials using this prime/boost approach. Additional investigations are warranted to optimize DNA plasmid delivery methods, such as electroporation for priming of DNA–protein combinations.