Immunogenicity and Safety of a Purified Vero Rabies Vaccine-Serum Free, Compared With 2 Licensed Vaccines, in a Simulated Rabies Post-Exposure Regimen in Healthy Adults in France: A Randomized, Controlled, Phase 3 Trial

Abstract

Background: A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman-Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and the human diploid cell vaccine (HDCV; Imovax Rabies®).

Methods: This dual-center, modified, double-blind, phase 3 study evaluated the immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG) versus PVRV + HRIG and HDCV + HRIG in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N = 640) were randomized 3:1:1:1 to PVRV-NG2 + HRIG, PVRV + HRIG, HDCV + HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, D3, D7, D14, and 28, with HRIG on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA) titers were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2 + HRIG and PVRV + HRIG/HDCV + HRIG was >-5% at D28. Safety was assessed up to 6 months after the last injection.

Results: Non-inferiority of PVRV-NG2 + HRIG compared with PVRV + HRIG and HDCV + HRIG was demonstrated. Nearly all participants (99.6%, PVRV-NG2 + HRIG; 100%, PVRV + HRIG; 98.7%, HDCV + HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines.

Conclusions: In a simulated PEP setting, PVRV-NG2 + HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines.

Clinical trials registration: NCT03965962.

Keywords: PVRV-NG2; immunogenicity; post-exposure prophylaxis; rabies; safety.

Graphical Abstract

Figure 1.

Disposition of participants. *Two participants randomized to receive PVRV-NG2 alone were inadvertently given PVRV-NG2 + HRIG. The difference in N at each visit does not reflect N discontinued, as a small number of participants were absent for 1 visit but completed the active phase by attending an additional visit. One participant was absent for 1 visit and attended the next visit before discontinuation. Abbreviations: D, day; HDCV, human diploid cell vaccine; HRIG, human rabies immunoglobulin; M, month; PVRV, purified Vero cell rabies vaccine; PVRV-NG2, next-generation purified Vero cell rabies vaccine.

Figure 2.

Percentage of participants achieving RVNA titers ≥0.5 IU/mL at D14, D28, and D42 by vaccination group (per-protocol analysis set). Abbreviations: D, day; HDCV, human diploid cell vaccine; HRIG, human rabies immunoglobulin; PVRV, purified Vero cell rabies vaccine; PVRV-NG2, next-generation purified Vero cell rabies vaccine; RVNA, rabies virus neutralizing antibody.

Figure 3.

Rabies virus neutralizing antibody GMT at D14, D28, and D42 by vaccination group (per-protocol analysis set). Abbreviations: D, day; GMT, geometric mean titer; HDCV, human diploid cell vaccine; HRIG, human rabies immunoglobulin; PVRV, purified Vero cell rabies vaccine; PVRV-NG2, next-generation purified Vero cell rabies vaccine.

Figure 4.

Percentage of participants who experienced a solicited injection site reaction (A) or solicited systemic reaction (B) within 7 days after any vaccine injection (safety analysis set). Abbreviations: HDCV, human diploid cell vaccine; HRIG, human rabies immunoglobulin; PVRV, purified Vero cell rabies vaccine; PVRV-NG2, next-generation purified Vero cell rabies vaccine.