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.

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.

Safety and immunogenicity of an investigational meningococcal ACWY conjugate vaccine (MenACWY-CRM) in healthy Indian subjects aged 2 to 75 years.

BACKGROUND: This phase 3, multi-center, open-label study evaluated the immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM, Menveo(®); Novartis Vaccines and Diagnostics S.r.l., Siena, Italy) in healthy Indian subjects aged 2-75 years, to provide data for licensure in India. METHODS: A total of 180 subjects were enrolled (60 subjects 2-10 years, 60 subjects 11-18 years, and 60 subjects 19-75 years) and received one dose of MenACWY-CRM. Serum bactericidal activity with human complement (hSBA) was measured before and 1 month after vaccination. Adverse events were collected throughout the 29-day study period. RESULTS: Percentages of subjects with post-vaccination hSBA ≥8 were 72%, 95%, 94%, and 90% for serogroups A, C, W, and Y, respectively. Geometric mean titers rose 7-fold to 42-fold against the four serogroups. Similar immune responses were observed for the age subgroups 2-10 years, 11-18 years, and 19-75 years. Seroresponse rates at 1 month following vaccination were 72%, 88%, 55%, and 71% for serogroups A, C, W, and Y, respectively. The vaccine was well tolerated with no safety concerns. CONCLUSION: A single dose of MenACWY-CRM induced a robust immune response against all four meningococcal serogroups and was well tolerated in an Indian population 2-75 years of age.

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.

A phase III single arm, multicenter, open-label study to assess the immunogenicity and tolerability of a pentavalent DTwP-HepB-Hib vaccine in indian infants.

Compliance with recommended vaccinations for Indian infants is facilitated by using combination vaccines to minimize the number of required injections. The ready-to-use, preservative free, fully-liquid combination DTwP-HepB-Hib vaccine, Quinvaxem(®), offers convenience of administering five important vaccine antigens to infants in a single injection. This phase III, single-arm, multicenter study was designed to assess immunogenicity and safety of three doses of Quinvaxem(®) to Indian infants administered at 6, 10, and 14 weeks of age. Blood samples were taken prior to the first dose and at one month post last vaccination. Infants were observed clinically for any reaction approximately 30 min following each vaccination, and parents completed subject diaries for solicited local, systemic and any adverse events (AEs) following over a 5 d period. DTwP-HepB-Hib vaccine elicited strong immune responses that exceeded seroprotection/seroconversion thresholds against all vaccine antigens. At one month after third vaccination, percentages of infants achieving predefined protective antibody levels were 99% diphtheria; 100% tetanus; 98% Hepatitis B; 100% Hib short-term (≥ 0.15 µg/mL); 95% Hib long-term (≥ 1.0 µg/mL) protection; and relevant immune response was 99% for pertussis. The vaccine was well tolerated, with no vaccine-related serious AEs. Only one case of high fever (≥ 40 °C) was reported. The most frequently reported reactions were mild to moderate tenderness and erythema. Frequencies of all AEs declined with subsequent vaccinations. This study demonstrated that this convenient, fully-liquid DTwP-HepB-Hib vaccine is highly immunogenic and has a acceptable safety profile for use in Indian infants. ClinicalTrials.gov Identifier: NCT01470287. Clinical Trials Registry of India Number: CTRI/2011/11/002118.

Rabies pre-exposure vaccination of children with purified chick embryo cell vaccine (PCECV).

Human rabies, mainly transmitted by dog bites, remains a major public health problem in developing countries. In Asian countries, such as India or the Philippines, where large free-ranging dog populations exist, the human death toll stays high. Children under the age of 15 y are at particular risk, representing up to half of the dog bite victims. While pre-exposure prophylaxis (PrEP) is commonly used in travelers from developed countries visiting areas of high endemicity, rabies vaccination is rarely used in highly endemic countries in contrast to post-exposure prophylaxis (PEP). Purified Chick Embryo Cell Vaccine (PCECV, Rabipur®/RabAvert®, Novartis Vaccines and Diagnostics) is approved for pre- and post-exposure prophylaxis, either by the intramuscular route, or--where registered--by the intradermal route of administration. In more than 25 y of use, PCECV has been widely used for PrEP in children. This review summarizes the pediatric pre-exposure clinical trials using PCECV. In total, PCECV has been administered to more than 1,200 children in clinical trials, from toddlers to those in elementary school, using intramuscular and intradermal schedules, demonstrating safety and immunogenicity. PrEP as part of routine pediatric vaccination programs may have a major role to play in human rabies prevention. Extensive clinical experience with PCECV supports intramuscular and intradermal PrEP in children as one pillar of human rabies prevention in developing countries.

Protecting Indian schoolchildren against rabies: pre-exposure vaccination with purified chick embryo cell vaccine (PCECV) or purified verocell rabies vaccine (PVRV).

Although rabies can be effectively prevented by means of preexposure or post-exposure prophylaxis, in India, an estimated 17,000 to 20,000 human rabies deaths occur annually. Tragically, 50% of these victims are children under the age of 15. In addition to immediate post-exposure prophylaxis measures, including active and passive immunization, pre-exposure vaccination using tissue culture vaccines is a safe and effective but highly underutilized method of preventing rabies in humans living or working in areas at risk. This study assessed the safety and immunogenicity of Purified Chick Embryo Cell Vaccine (PCECV) and Purified Verocell Rabies Vaccine (PVRV), administered as a three-dose intramuscular pre-exposure regimen on days 0, 7 and 28 in 175 healthy schoolchildren. PCECV was administered after reconstitution using either 1.0 mL or 0.5 mL (half the diluent volume) and PVRV was given after reconstitution with 0.5 mL. Vaccine safety was assessed observer-blind, including pain assessment with a validated visual analogue scale for children. Rabies virus neutralizing antibody (RVNA) concentrations were measured on day 49 by RFFIT. All children developed adequate RVNA concentrations above 0.5 IU/mL. Solicited local and systemic reactions were within the range expected, pain after vaccination was reported in 2 to 12% of study subjects, fever was reported in 2 to 5%. There was no statistical difference by vaccination group or vaccination day. No unexpected or serious adverse event was reported during the study. In conclusion, PCECV and PVRV are safe and immunogenic when administered intramuscularly for pre-exposure prophylaxis of rabies in children. A 1.0 mL dilution volume for PCECV was as well tolerated as PVRV or PCECV reconstituted in half the volume.

Comparison of saftey 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 at two sites 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.

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.