•Phase II trial evaluating efficacy and safety of candidate rabies vaccine. PVRV-NG.•PVRV-NG was compared with Imovax® Rabies (HDCV) in healthy children and adolescents.•The RVNA seroconversion rate was non-inferior in those receiving PVRV-NG vs HDCV.•Reported adverse events were similar between treatment groups.•PVRV-NG is expected to offer similar clinical protection and safety profile to HDCV. A serum-free, highly purified Vero rabies vaccine (PVRV-NG) has been developed with no animal or human components and low residual DNA content. A phaseII randomized clinical study aimed to demonstrate the non-inferiority of the immune response and assess the safety profile of PVRV-NG versus a licensed human diploid cell culture rabies vaccine (HDCV) in a pre-exposure regimen in healthy children and adolescents in the Philippines. Children aged 2–11 years and adolescents aged 12–17 years were randomized (2:1) to receive three injections of either PVRV-NG or HDCV (on day D 0, D7 and D28). Rabies virus-neutralizing antibodies (RVNA) were measured at D0, D42 and 6 months after the first injection (month M 6). Safety was assessed during the vaccination period and up to 28 days after the last vaccination. Serious adverse events were followed until 6 months after last vaccination. 342 healthy participants (171 children and 171 adolescents) were randomized and followed for 6 months after the last dose. All participants in both groups had an RVNA titer ≥ 0.5 IU/ml at D42, demonstrating non-inferiority in seroconversion rate for PVRV-NG versus HDCV. Over 90% of participants had RVNA titer ≥ 0.5 IU/ml at M6. PVRV-NG was well tolerated after each vaccination and up to 6 months following the last dose. There were no major safety concerns during the study, and the type and severity of solicited adverse events was similar for both treatment groups. This study demonstrated the non-inferior immune profile of PVRV-NG compared with HDCV in a pre-exposure setting within a pediatric population. PVRV-NG was well tolerated with no safety concerns. This study is registered at ClinicalTrials.gov (NCT01930357) and EU Clinical Trials Register (2015–003203-30).