The Zagreb and Essen regimens are comparable in terms of immunogenicity
however, how these regimens impact the immunogenicity of booster vaccination remains unknown. We conducted a clinical trial to assess the immunogenicity of booster vaccination with a purified Vero cell rabies vaccine after primary vaccination with the Zagreb or Essen regimens. This randomized, open-label, controlled, phase 3 trial, conducted in Shangyu City and Shengzhou City, Zhejiang Province, China, was divided into the primary and booster vaccination phases. After screening, all eligible participants were allocated to groups A, B, C, D, E, or F. Groups A, B, and C received the Zagreb regimen as the primary vaccine, while groups D, E, and F received the Essen regimen. The booster vaccination was conducted 6 months after the primary vaccination. Groups B and E received one dose of the booster, while groups C and F received two doses. Blood samples were collected before the booster, at 14 days after the booster, and at approximately 6 months after the booster. Safety was assessed from the first booster dose to 6 months after the final dose. A total of 718 participants completed the booster vaccination. The antibody positive rate (APR) of groups B, C, E, and F after the booster was 100%. The antibody titer rose significantly even after one booster, and was much higher in groups B (48.80 IU/ml) and C (64.38 IU/ml) (receiving Zagreb) than in groups E (34.25 IU/ml) and F (42.89 IU/ml) (receiving Essen). Although the incidence of ARs was higher in groups B (11.22%) and C (15.79%) than in groups E (3.68%) and F (10.87%), they were all mild and short-lived. No serious adverse events (SAEs) associated with vaccination were reported. The immunogenicity of booster vaccination after the Zagreb regimen was significantly higher than that after the Essen regimen. One booster may be sufficient to raise the antibody titer above the 0.5 IU/mL target.Clinical trial registration: This trial is registered at http://www.chinadrugtrials.org.cn/index.html under the registration number CTR20210426 at 08/03/2021.