Comparison of the immunogenicity and safety of the purified chick embryo cell rabies vaccine manufactured in India and Germany: A randomized, single blind, multicentre, phase IV clinical study

Abstract

This phase IV, single blind study assessed the immunogenicity and safety of India-manufactured purified chick embryo cell rabies vaccine (PCECV), compared with a German-manufactured batch obtained by the same production process. A total of 340 participants enrolled at 2 study sites in India were randomized (1:1:1:1) in 4 groups to receive a 5-dose Essen regimen with either 1 of the 3 Indian batches (PCECV-I) or the German batch (PCECV-G), administered on Days (D) 0, 3, 7, 14 and 30. The lot-to-lot consistency of PCECV-I batches in terms of induced immune response at D14 was demonstrated. The immune response elicited by PCECV-I was shown to be non-inferior to that induced by PCECV-G, as the lower limit of the 95% confidence interval for the ratio (PCECV-I/PCECV-G) of rabies virus neutralising antibody (RVNA) geometric mean concentrations was higher than 0.5 at D14. At least 96% of participants developed adequate RVNA concentrations (≥ 0.5 IU/mL) by D14 and all achieved RVNA concentrations ≥ 0.5 IU/mL by D90. RVNA levels were comparable across all groups throughout the entire study. Solicited local and general symptoms had a similar incidence in all groups. Unsolicited adverse events (AEs) were reported by 11% of participants. Only 1 serious AE (leg fracture) was reported and was not related to vaccination. No deaths and no rabies cases were recorded during the 90 days of observation. The study showed that the 3 PCECV-I and the PCECV-G batches induced a similar immune response and had a comparable safety profile when administered according to a 5-dose schedule.

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

“…The proportions of participants from the concomitant HRIG groups who achieved RVNA titers ≥0.5 IU/mL 14 days after the first vaccination (between 88.0% and 94.1%) are consistent with the findings of previous studies that assessed licensed rabies vaccines in healthy participants or participants with suspicion of rabies exposure [ 5 , 25 , 29–33 ]. Some participants in those previous studies also failed to achieve RVNA titers ≥0.5 IU/mL, regardless of the rabies vaccine used, and with different PEP regimens [ 30–34 ]. This is supported by the experience in reference laboratories where between 1.4% and 13% of participants do not reach the threshold [ 32 , 35 , 36 ] and by previous studies conducted during the clinical development of PVRV-NG (WHO universal trial number U1111–1117–7447; manuscript in development) [ 15 ].…”

Safety and immunogenicity of three dose levels of an investigational, highly purified Vero cell rabies vaccine: A randomized, controlled, observer-blinded, Phase II study with a simulated post-exposure regimen in healthy adults

“…This effect has been observed in several studies, which noted that co-administration of licensed rabies vaccines with HRIG resulted in rates of 91–99% of patients achieving an RVNA titer ≥0.5 IU/mL at D14, without impact on the effectiveness of the vaccines. 29 – 30-34 – 37 Currently, WHO guidelines recommend that RIGs be injected only around the wound in exposed patients, with IM injection of the remaining rabies RIG no longer recommended. 17 As such, the co-administration of HRIG in this simulated PEP regimen was the most stringent evaluation of the rabies vaccines since a full dose was injected into the participants’ adjacent thigh – with the practice of delivering excess HRIG by IM at a site distant from vaccine administration adopted globally.…”

Inhibitory effect of concomitantly administered rabies immunoglobulins on the immunogenicity of commercial and candidate human rabies vaccines in hamsters

“…In PEP regimen with co-administration of RIG, the delay in immune response development to rabies vaccine may be increased due to transient immuno-suppressive effect of the RIG regardless of the vaccination regimen used. Results from clinical trials have shown seroconversion ranging between 80 and 100% at Day 14, whereas in real-world observational cohort studies the seroconversion ranged between 93 and 100% even at Day 28 using IM PEP regimens with different licensed vaccines co-administered with RIG 8 – 16 . These data indicate that, in clinical trials and observational studies, seroconversion of 100% was not always achieved at Day 14 when RIG was co-administered with the vaccine.…”