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Background: The next generation (serum-free) rabies vaccine has been under development progress and shown good safety and immunogenicity profiles. A reduced 4-dose vaccine schedule, replacing the previously recommended 5-dose schedule, has been recommended for postexposure prophylaxis (PEP) to prevent human rabies. Methods: A randomized, double-blind, active-controlled phase Ⅰ/Ⅲ clinical trial in participants aged 10-60 years was conducted to evaluate the immunogenicity and safety of Sinovac serum-free rabies vaccine using 4-dose and 5-dose immunization schedules, in comparison with a licensed rabies vaccine in a simulated PEP setting. In the first part (phase Ⅰ), participants received five doses of Sinovac rabies vaccine on days 0, 3, 7, 14, 28 (5-dose schedule; D0, 3, 7, 14, 28) to preliminarily evaluate the safety. In the second part (phase Ⅲ), participants were randomized to four groups in a 1:1:1:1 ratio to receive Sinovac rabies vaccine of two 4-dose schedules (on D0, 3, 7, 14 or D0, 3, 7, 28) and 5-dose schedule, as well as receive the licensed rabies vaccine of 5-dose schedule. Rabies virus neutralizing antibodies (RVNA) titers were tested on days 0, 14, 28, 42, as well as on 3 and 6 months after the last dose. Immune non-inferiority and persistency and safety through to 6 months after the last dose were assessed in the second part. Results: A total of 2040 healthy participants were enrolled, with 40 and 2000 participants in the first and second part, respectively. Non-inferiority of Sinovac rabies vaccine compared with the licensed rabies vaccine was demonstrated, with the 95% lower limit confidence intervals (LLCI) of seroconversion rate differences ≥−5% on D14 and D42 and the geometric mean concentration (GMC) ratio ≥0.67 on D14. In the susceptible participants with RVNA <0.5 IU/mL on D0, the seroconversion rates of all three groups received Sinovac rabies vaccine were 100% by D14, and RVNA of 100% and at least 97.5% participants sustained ≥0.5 IU/mL through 3 and 6 months after the last dose. The safety profiles were similar across all groups, with most adverse reactions in Grade 1. There was no vaccine related serious adverse events reported. Conclusions: Sinovac serum-free rabies vaccine, when administered under the 5-dose or reduced 4-dose schedules, was non-inferior to the licensed rabies vaccine of 5-dose schedule, with no safety concerns identified.