A randomized open-labeled study to demonstrate the non-inferiority of purified chick-embryo cell rabies vaccine administered in the Zagreb regimen (2-1-1) compared with the Essen regimen in Chinese adults

Abstract

The Zagreb regimen has been used for 20 years in various countries. In China, until 2010, the Zagreb schedule was only approved for purified chick embryo cell vaccine (PCECV) and purified Vero cell rabies vaccines (PVRV). In this phase III clinical trial, we aimed to demonstrate the safety and immunogenic non-inferiority of the Zagreb regimen compared with the Essen regimen in healthy adult Chinese immunized with PCECV (Rabipur®). The study enrolled 825 subjects aged 18 to 50 years; serum samples were collected on Days 0, 7, 14, 42, and at 13 months to assess rabies virus neutralizing antibody (RVNA) concentrations. Solicited and unsolicited local and systemic reactions were recorded for 6 days following the day of vaccination, and collected throughout the entire study period (Day 1 until Month 13). The Zagreb regimen was non-inferior to the Essen regimen with regard to RVNA concentrations after 7, 14, and 42 days, and 13 months of immunization. The non-inferiority of seroconversion was established at Days 14 and 42. The incidence of local and systemic reactions was similar between groups, and mostly of mild or moderate severity. Vaccine-related adverse events occurred more frequently in the Essen group than in the Zagreb group. Vaccination with PCECV under a 2-1-1 regimen is as safe and immunogenic as under the traditional 5-dose Essen regimen for rabies post-exposure prophylaxis, and is a more cost-effective option, has a more practical vaccination schedule, and can potentially increase compliance.

Trial registration: ClinicalTrials.gov NCT00825305 NCT01067079.

Keywords: AE; Food and Drug Administration; GMC; PCECV; World Health Organization; Zagreb regimen; adverse event; CCEEV; cell culture or embryonated egg-based rabies vaccines; CI; chick-embryo cells; confidence interval; FDA; geometric mean concentration; HDCV; human diploid cell rabies vaccine; PCECV; immunogenicity; neutralizing antibody; per protocol set; PrEP; post-exposure prophylaxis; PPS; pre-exposure prophylaxis; PVRV; purified Vero cell rabies vaccine; RFFIT; purified chick embryo cell rabies vaccine; PDEV; purified duck embryo cell vaccine; PEP; rabies vaccine; rabies virus neutralizing antibody; SAE; rapid fluorescent focus inhibition test; RVNA; safety; serious adverse event; WHO.

Figures

Figure 1.

Flow diagram of the trial.

Figure 2.

Rabies virus neutralizing antibody concentrations (GMC) in the Zagreb and Essen groups (PP set) on Days 7, 14, 42, and Month 13. Error bars and values in parenthesis represent 95% CI. *Dotted reference line: the WHO recommends a specific antibody level of 0.5 IU/ml as being indicative of an adequate immune response after vaccination.

Figure 3.

Rates of seroconversion (defined as RVNA ≥ 0.5 IU/mL) in the Zagreb and Essen groups (PP set) on Days 7, 14, 42, and Month 13 month. Error bars and values in parenthesis represent 95% CI.