Purified Chick Embryo Cell Rabies Vaccine Research Articles

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

ABSTRACTThis 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 purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: A randomized open-label study

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016.

Comparative study on the immunogenicity and safety of a purified chick embryo cell rabies vaccine (PCECV) administered according to two different simulated post exposure intramuscular regimens (Zagreb versus Essen)

Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO-recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of ≥ 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857

Antibody response to an eight-site intradermal rabies vaccination in patients infected with Human Immunodeficiency Virus

Objective To investigate the rabies virus neutralizing antibody response in HIV-1-infected patients with CD4+ cell count ≤200 cells/μL or >200 cells/μL after post-exposure prophylaxis using an eight-site intradermal rabies vaccination regimen. Methods In a prospective cohort study, 27 HIV-1 infected patients were recruited, none of which had a history of rabies vaccination. All patients provided informed consent and were separated into two groups according to their CD4+ cell count (patients with CD4+ counts of ≤200 cells/μL and patients with CD4+ counts of >200 cells/μL). All patients received Purified Chick Embryo Cell rabies Vaccine (PCECV) using a modified eight-site regimen in which 0.1 mL of vaccine was injected intradermally on each of days 0, 3, 7, 14, and 30 (8–8–8–8–8). CD4+ cell counts, HIV-1 viral load and rabies virus neutralizing antibody (RVNAb) concentrations as determined by the Rapid Fluorescent Focus Inhibition Test (RFFIT) were evaluated on blood samples taken on days 0, 3, 7, 14, 30, 90, 180 and 365 after vaccination. Results Of the 27 patients included in the study, 18 patients (67%) had CD4+ cell counts of >200 cells/μL and 9 patients (33%) had CD4+ counts of ≤200 cells/μL. No patients had detectable RVNAb concentrations on day 0. By day 14, all patients had adequate RVNAb concentrations (≥0.5 IU/mL). There was no statistically significant difference in RVNAb concentrations between the two groups on days 3, 7, 14, 30, 90, 180 and 365 after vaccination. Conclusion PCECV is immunogenic in HIV-1-infected patients with CD4+ cell counts below 200 cells/μL when administered in a modified eight-site intradermal PEP regimen.

Comparison of Safety and Immunogenicity of Purified Chick Embryo Cell Rabies Vaccine (PCECV) and Purified Vero Cell Rabies Vaccine (PVRV) Using the Thai Red Cross Intradermal Regimen at a Dose of 0.1 ML

Intradermal (ID) vaccination with modern cell culture rabies vaccines is a means to significantly reduce the cost of post-exposure prophylaxis as compared to intramuscular vaccination. In this study we evaluated the efficacy, immunogenicity and tolerability of PCECV and PVRV administered ID in doses of 0.1 mL per site according to the 2-site Thai Red Cross (TRC) regimen. Patients with WHO category III exposure to suspect or laboratory proven rabid animals were administered either PCECV (n=58) or PVRV (n=52) ID at a dose of 0.1 mL per site on days 0, 3 and 7 and at one site on days 30 and 90. Serum samples were withdrawn on days 0, 14, 30, 90, and 180 and rabies virus neutralizing antibody (RVNA) titers were determined by rapid fluorescent focus inhibition test (RFFIT). Patients who were exposed to laboratory confirmed rabid animals were followed up for one year after exposure. All 110 patients developed RVNA titers above 0.5 IU/mL by day 14. Adequate titers >0.5 IU/mL were maintained up to day 180. Both vaccines induced equivalent RVNA titers at all time points and were well tolerated. Five subjects who were bitten by laboratory confirmed rabid dogs were alive and healthy one year after exposure. As demonstrated, PCECV and PVRV are both immunogenic, efficacious and well tolerated when administered in the TRC post-exposure prophylaxis regimen in ID doses of 0.1 mL as recommended by WHO guidelines. The use of PCECV in this regimen may prove more economical in developing countries like India.

The influence of homologous vs. heterologous challenge virus strains on the serological test results of rabies virus neutralizing assays

The effect that the relatedness of the viral seed strain used to produce rabies vaccines has to the strain of challenge virus used to measure rabies virus neutralizing antibodies after vaccination was evaluated. Serum samples from 173 subjects vaccinated with either purified Vero cell rabies vaccine (PVRV), produced from the Pittman Moore (PM) seed strain of rabies virus, or purified chick embryo cell rabies vaccine (PCECV), produced from the Flury low egg passage (Flury-LEP) seed strain of rabies virus, were tested in parallel assays by RFFIT using a homologous and a heterologous testing system. In the homologous system, CVS-11 was used as the challenge virus in the assay to evaluate the humoral immune response in subjects vaccinated with PVRV and Flury-LEP was used for subjects vaccinated with PCECV. In the heterologous system, CVS-11 was used as the challenge virus in the assay to evaluate subjects vaccinated with PCECV and Flury-LEP was used for subjects vaccinated with PVRV. Although the difference in G protein homology between the CVS-11 and Flury-LEP rabies virus strains has been reported to be only 5.8%, the use of a homologous testing system resulted in approximately 30% higher titers for nearly two-thirds of the samples from both vaccine groups compared to a heterologous testing system. The evaluation of equivalence of the immune response after vaccination with the two different vaccines was dependent upon the type of testing system, homologous or heterologous, used to evaluate the level of rabies virus neutralizing antibodies. Equivalence between the vaccines was achieved when a homologous testing system was used but not when a heterologous testing system was used. The results of this study indicate that the strain of virus used in the biological assays to measure the level of rabies virus neutralizing antibodies after vaccination could profoundly influence the evaluation of rabies vaccines.

Reducing the cost of post-exposure rabies prophylaxis: efficacy of 0.1 ml PCEC rabies vaccine administered intradermally using the Thai Red Cross post-exposure regimen in patients severely exposed to laboratory-confirmed rabid animals

Purified chick embryo cell rabies vaccine (PCECV) administered as 0.1 ml intradermally according to the Thai Red Cross (TRC) regimen could reduce the cost of PEP by up to 84% when compared to the traditional five-dose Essen regimen. To confirm the efficacy of 0.1 ml of PCECV using the TRC regimen, a clinical trial was conducted in 113 patients presenting with category III exposures from confirmed rabid animals at two bite referral centres in the Philippines. Patients were monitored monthly for 1 year after exposure. PCECV was well tolerated, no vaccine-related serious adverse events occurred and all patients were alive 1 year after their initial exposure.

Rabies post-exposure prophylaxis in malnourished children exposed to suspect rabid animals

Over half of the world's malnourished children live in Asia where more than 90% of reported human rabies deaths occur. In order to determine the effect of malnutrition on the immune response to rabies post-exposure prophylaxis (PEP), 45 children with moderate to severe protein energy malnutrition (PEM) who were exposed to potentially rabid animals were enrolled in a clinical trial. Patients received purified chick embryo cell rabies vaccine (PCECV) on days 0, 3, 7, 14 and 30. Blood was drawn on days 0, 14 and 30 and evaluated for the presence of rabies virus neutralizing antibody. All children that met the protocol criteria developed rabies virus neutralizing antibody titers above the acceptable level of 0.5 IU/mL by day 14 and no serious adverse events were reported. We conclude that children in this study that received four or five doses of rabies vaccine intramuscularly developed an acceptable immune response despite their severe degree of protein energy malnutrition.

A comparison of the tolerability of two dilution volumes (0.5 mL and 1.0 mL) of a purified chick embryo cell rabies vaccine administered intramuscularly to healthy adult volunteers: A randomized, intraindividual, assessor-blind study

Background: The current recommendation of the manufacturer for administering purified chick embryo cell rabies vaccine (PCECV) is to reconstitute the contents with 1.0 mL of water for injection (WFI). However, it has been debated whether a lower volume of WFI (0.5 mL) is likely to cause less pain. Objectives: The aims of this study were to compare the tolerability of PCECV administered IM at a volume of 0.5 mL versus 1.0 mL of diluent and to determine the immunogenicity of the vaccine when administered according to the World Health Organization-recommended preexposure prophylaxis regimen for rabies immunization. Methods: This comparative, intraindividual, assessor-blind study was conducted at the Department of Clinical Pharmacology, Topiwala National Medical College and Bai Yamunabai Laxman Nair Charitable Hospital Mumbai, India). Healthy volunteers aged 18 to 50 years received, by randomized sequence, 3 IM injections of PCECV, diluted in 0.5 mL or 1.0 mL of WFI, on study days 0, 7, and 28. Tolerability was assessed at 30 minutes and 24 hours after injection and included assessments for local and systemic reactions. For immunogenicity assessment, rabies virus-neutralizing antibody 0RVNA) titers were assayed at baseline and on day 49 (ie, 3 weeks after the third injection). Results: Twenty-six subjects (24 men, 2 women; mean [SD] age, 22.4 [2.4] years; mean [SD] body weight, 59.0 [11.3] kg) entered the study. Twenty-five subjects were included in the tolerability assessment; 24 in the immunogenicity assessment. No statistically significant differences were found between dilutions in the frequency of local and systemic reactions. Most reactions were mild. All subjects developed RVNA titers >0.5 IU/mL (indicative of protection) by day 49. Conclusions: In this population of healthy volunteers, a full antigenic dose of PCECV in a dilution of 0.5 mL WFI is as well tolerated locally and systemically as in a dilution of 1.0 mL. All subjects developed levels of RVNA far exceeding 0.5 IU/mL, which is indicative of protection against rabies.

Reactogenicity and immunogenicity of the newly developed Purified Chick Embryo Cell (PCEC)-rabies vaccine in man

Purified Chick Embryo Cell (PCEC) rabies vaccine was given to 88 healthy adults according to six different vaccination schedules. Local side effects were reported on reactivity forms after 16.4% of PCECV injections, general symptoms were recorded after 15.1% of the 292 doses administered. IgE antibodies specific for chicken proteins determined by the Radio Allergo Sorbens Test (RAST) could not be shown before and after the vaccinations. With no exception, all 88 vaccinees developed high titres of complement-fixing and neutralizing antibodies as determined by the Rapid Fluorescent Focus Inhibition Test and Serum Mouse Neutralization Test. For the first time, induction of serum interferon by PCEC rabies vaccine has been shown in man. In rabies vaccination, PCEC vaccine seems to be as effective as Human Diploid Cell Strain (HDCS) vaccine.