Non-inferiority study of purified Vero rabies vaccine - serum free in three-dose and two-dose pre-exposure prophylaxis regimens in comparison with licensed rabies vaccines

Background: A next-generation, serum-free, highly purified Vero cell rabies vaccine, PVRV-NG2, is in development.

Methods: This multicenter, observer-blind, phase 3 study evaluated the immunogenicity and safety of PVRV-NG2, compared with two licensed rabies vaccines (purified Vero cell rabies vaccine [PVRV] and human diploid cell vaccine [HDCV]), as a pre-exposure prophylaxis (PrEP) regimen. Participants were randomized 3:1:1 to PVRV-NG2, PVRV, or HDCV, as a three-dose (Cohort 1; children and adults; day [D] 0, D7, and D28) or two-dose (Cohort 2; adults; D0 and D7) PrEP regimen. The primary objective was non-inferiority of PVRV-NG2 to PVRV and HDCV as three-dose PrEP, based on the proportion of participants with rabies virus neutralizing antibody (RVNA) titer ≥0.5 IU/mL at D42. Non-inferiority of immune response for two-dose PrEP at D28, and non-inferiority of two-dose (D28) versus three-dose (D42) HDCV were also assessed as secondary immunogenicity objectives. Safety was assessed throughout.

Results: Overall, 1708 participants were enrolled (Cohort 1: 505 children, 505 adults; Cohort 2: 698 adults). All participants had RVNA titers ≥0.5 IU/mL after three-dose PVRV-NG2 (D42), with non-inferiority to PVRV and HDCV demonstrated. All secondary immunogenicity objectives were achieved, including non-inferiority of two-dose PVRV-NG2 versus two-dose PVRV and HDCV (D28) and three-dose HDCV (D42), and non-inferiority of two-dose HDCV versus three-dose HDCV. The safety profile of PVRV-NG2 was comparable to those of PVRV and HDCV.

Conclusions: This study supports the use of PVRV-NG2 in two- or three-dose PrEP regimens, with no safety concerns identified.

Clinical trials registration: ClinicalTrials.gov identifier: NCT04127786; EudraCT: 2019-000973-22; WHO: U1111-1217-3241.