A serum-free, purified vero cell rabies vaccine is safe and as immunogenic as the reference vaccine Verorab™ for pre-exposure use in healthy adults: Results from a randomized controlled phase-II trial

ArticleinVaccine 31(18) · March 2013with32 Reads
DOI: 10.1016/j.vaccine.2013.02.058 · Source: PubMed
Abstract
Background: Verorab was licensed in 1985 for both pre- and post-exposure prophylaxis of rabies. The next generation purified Vero cell rabies vaccine (PVRV-NG) is a highly purified vaccine. We performed a phase II clinical study in adults in France to assess its immunological non-inferiority and clinical safety for pre-exposure prophylaxis. Methods: In a randomized phase-II trial, 384 healthy adult subjects were randomized (2:1) to receive a three-dose primary series of PVRV-NG or Verorab. One year later, the PVRV-NG group received a PVRV-NG booster while the Verorab group participants were randomized to receive a booster of PVRV-NG or Verorab for. Rabies virus neutralizing antibodies (RVNA) were evaluated on days 0, 28 (subgroup), 42, months 6, 12 and 12+14 days. Safety was evaluated for seven days after each dose. Adverse event between doses, until 28 days after the final dose was recorded. Serious adverse events were recorded up to 6 months after the last dose. Results: The criterion for non-inferiority was met in the per-protocol analysis set and confirmed in the full analysis set (FAS). In the FAS, 99.6% and 100% of subjects had RVNA titers ≥0.5 IU/mL in PVRV-NG and Verorab groups, respectively. While RVNA levels gradually decreased over the 12-month period, at 6 and 12 months after vaccination >89% and >77%, respectively, in both groups had RVNA titers ≥0.5 IU/mL. The PVRV-NG booster induced a strong response, irrespective of the vaccine given for the primary series. PVRV-NG was safe and well tolerated and its safety profile was similar to Verorab for unsolicited adverse events and solicited systemic reactions. The incidence of solicited injection-site reactions was lower with PVRV-NG than with Verorab after the primary series and the booster dose. Conclusions: PVRV-NG was shown to be at least as immunogenic as Verorab and to present a similar safety profile.
    • "Dual targeting of TLRs induces synergistic increases in Ag-specific neutralizing antibodies[7]. Vero cells have been used in vaccine production since 1980s[8][9][10][11][12][13][14][15], however, the oncogenic long-fragment residual DNA from vero cell substrates pose a potential risk to human health [16][17][18]. Thus, nucleases, such as Benzonase manufactured by Merck & Co., were used to digest long-fragment DNA into short-fragment DNA (sf-DNA)[19, 20] which was assumed with better safety[21]. "
    [Show abstract] [Hide abstract] ABSTRACT: To reduce potential oncogenic long genomic DNA in vaccines, nuclease treatment has been applied in the purification processes. However, this action increased the residue of short-fragment DNA and its effect on vaccine potency was still elusive. In this study, we found residual sf-DNA in an inactivated EV71 vaccine could enhance humoral immune response in mice. Ag stimulation in vitro and vaccine injection in vivo revealed that TLR9 transcription level was elevated, indicating that sf-DNA could activate TLR9. These new findings will help us to understand the molecular mechanism induced by vero-cell culture-derived vaccines.
    Full-text · Article · Apr 2016
    • "Animal cell cultures have been used for the production of rabies vaccines since the 1960s due to the neurological deleterious effects caused by first-generation vaccine based on the application of animal nervous tissue [1]. According to World Health Organization (WHO), these vaccines contain an inactivated virus and can be developed in various cell substrates such as human diploid cells, primary chicken embryo cells, Vero cells, or in primary Syrian hamster kidney cells. "
    [Show abstract] [Hide abstract] ABSTRACT: This work objective was to define a modeling approach based on genetic algorithm (GA) for optimizing parameters of an artificial neural network (ANN); the latter describes rabies virus production in BHK-21 cells based on empirical data derived from uniform designs (UDs) with different numbers of experimental runs. The parameters considered for viral infection were temperature (34 and 37. °C), multiplicity of infection (0.04, 0.07, and 0.1), infection, and harvest times (24, 48, and 72. h), with virus production as the monitored output variable. A multilevel factorial experimental design was performed and used to train, validate, and test the ANN. Its experimental fractions (18, 24, 30, 36, and 42 runs) defined by UDs were used to simulate the neural architectures. In GA, the neural computing parameters constituted the population individuals, and the steps involved were population creation, selection, and replacement by crossover and mutation. The ANN optimized by the combined algorithm showed a good calibration for all UDs under consideration, thus demonstrating to be suitable (R >. 0.85) as a correlation method in UDs independent of the experimental runs developed. Therefore, this work could guide researchers in the efficient use of UDs in the simulation and optimization of virus production processes.
    Article · Dec 2015
    • "Moreover, PVRV-NG complies with the European Union pharmacopeia and the specifications defined by the WHO and the US Food and Drug Administration (FDA). As was already shown for pre-exposure in a Phase II trial [5], this Phase III trial demonstrated the immunogenic non-inferiority of PVRV-NG compared with Verorab after three doses of a postexposure regimen, with regards to RVNA titers in healthy subjects aged 10 years and over, regardless of gender, pre-vaccination titer and age. All subjects reached the 0.5 IU/mL seroconversion threshold after three doses, apart from one subject in the PVRV-NG group and one in the Verorab group who reached the threshold after completion of the full schedule. "
    [Show abstract] [Hide abstract] ABSTRACT: As an evolution of its currently licensed rabies vaccine Verorab(®), Sanofi Pasteur has developed a next-generation, serum-free, highly purified Vero rabies vaccine (PVRV-NG). Through this Phase III clinical trial, we aimed to demonstrate the non-inferiority of PVRV-NG over Verorab when administered according to a post-exposure regimen and to assess its clinical safety. A total of 816 healthy subjects aged ≥10 years were randomized according to a 2:1 ratio to receive PVRV-NG or Verorab. Half of the subjects were aged 10-17 years, the other half were aged ≥18 years. All subjects were to receive 5 injections on days 0, 3, 7, 14 and 28. Three blood samples were taken for rabies virus neutralizing antibodies (RVNA) assessment, at baseline, on day 14 and day 42. Solicited adverse reactions (between injections 1, 2 and 3, and within 7 days post-injections 4 and 5) and adverse events (up to 28 days after the last injection) were collected for clinical safety assessment; serious adverse events were reported up to 6-months after the last injection. The proportion of subjects with an RVNA titer ≥0.5IU/mL after the third injection of PVRV-NG was non-inferior to the proportion of those who received Verorab. PVRV-NG was shown to be as immunogenic as Verorab in each age range in the per-protocol and full analysis sets. PVRV-NG induced a strong immune response in both age ranges, with high RVNA levels and increased geometric mean titers compared to baseline after each measured time point. PVRV-NG had a satisfactory safety profile after each injection, similar to Verorab with regards to the nature, frequency, duration and severity of adverse events. Two serious adverse events were reported, none was related to vaccination. This trial demonstrated the immunogenic non-inferiority of PVRV-NG over Verorab and showed that both vaccines have similar safety profiles. This trial is registered at ClinicalTrials.gov (NCT01339312). This manuscript is the first full report of the study. An abstract of the study results was previously presented at the Rabies in the Americas (RITA) conference in October 2012 in São Paulo, Brazil. Sanofi Pasteur.
    Full-text · Article · Oct 2013
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