Status: approvals withdrawn

Organizations involved:

Sanofi Pasteur Ltd. – Former

Sanofi Pasteur Inc. – Former

Sanofi Pasteur S.A. – Parent; Former

Wistar Institute – Former

Cross ref.: See the Rabies Vaccine Products entry (#525), and the entry below for Imovax, the rabies vaccine currently marketed by Sanofi Pasteur in the U.S.

Description: Rabies Vaccine or RABIE-VAX is a lyophilized (freeze-dried) formulation of inactivated rabies virus cultured in MRC-5 human diploid cells. The vaccine is prepared from the “fixed” CL-77 strain of rabies virus grown on monolayers of MRC-5 cells. Virus is concentrated by membrane filtration, inactivated with beta-propiolactone (BPL), and further purified by continuous gradient zonal centrifugation and dialysis. In addition to viral proteins, the vaccine contains up to 2% Albumin (Human) as a stabilizer.

The vaccine was supplied in packages containing 1 single dose vial of vaccine and 1 vial (1.1 mL) of Sterile Water for Injection for use as diluent (for a 1.0 mL dose inoculation) and intramuscular injection. Each dose contains less than 1 µg of bovine serum and traces of antibiotics (polymyxin and neomycin) originating from the cell culture medium. Less than 355 µg protein originating from the cell substrate may be present in the vaccine. The potency is ≥ 2.5 International Units (IU) of rabies antigen per 1.0 mL dose (as established by testing in parallel with the U.S. Standard Rabies Vaccine in the NIH mouse potency test).

Nomenclature: Rabies Vaccine/Sanofi Canada [BIO]; RABIE-VAX [TR]; Rabies Vaccine [FDA USAN]; Rabies Vaccine, Inactivated [FDA used on some approval documents]; Rabies Vaccine USP [USP]

Companies.: The vaccine was approved for manufacture by Aventis Pasteur Ltd., CBER/FDA est. lic. no. 0073, now Sanofi Aventis Ltd., a subsidiary of Sanofi Aventis S.A. It was marketed in U.S. by Connaught Labs., later Aventis Pasteur Inc., and perhaps marketed internationally by Aventis Pasteur S.A. affiliates. Aventis merged into Sanofi Aventis S.A. in late 2004.

Manufacture: The host cell line and culture process were developed by the Wistar Institute. The CL-77 rabies virus originated from the CD-60 fixed rabies virus strain developed from the SAD (Street Alabama Dufferin) rabies virus strain adapted to grow in MRC-5 cells.

Human diploid (MRC-5) cells are inoculated with seed virus. Each batch of cells is used to produce several viral harvests. The harvested fluids are clarified and inactivated with beta-propiolactone (BPL) and residual BPL is hydrolyzed. Purification of inactivated virus is carried out using continuous gradient zonal centrifugation, followed by dialysis. The viral antigen is banded by density gradient in a sucrose solution, and appropriate fractions removed. Albumin (Human) is added as a stabilizer to a final concentration of 2.0% of the pooled fractions. The fractions are stored for up to ten weeks at -65˚C until all testing is complete. Purified fractions are pooled and diluted to the desired potency. The bulk is sampled for potency, presence of residual rabies virus, sterility, and pH testing.

Virus culture and purification was performed by Connaught Ltd., later Aventis Pasteur Ltd., in Canada. The bulk was frozen and shipped to Connaught Labs., Inc., later Aventis Pasteur Inc. (Swiftwater, PA) for filing and lyophilization (freeze-drying) under a contract manufacturing agreement. Vials containing lyophilized Rabies Vaccine were capped and stored at 2-8˚C (refrigerated) until testing was complete. Final container samples were returned to Connaught/Aventis Pasteur Ltd. (Canada) for final testing prior to release including: general safety, potency, sterility, residual moisture, residual BPL, protein, pH, osmolality, and identity.

FDA class: Biologic PLA

CBER class: Viral And Rickettsial Vaccines

Approvals: Date = original approval date unknown (perhaps in the late 1970s)

Date = 19911227; first approval, PLA ref. no. 88-0284; granted to Connaught Labs. Ltd. (CLI; Canada), according to the CBER/FDA database. However, according to the FDA approval letter on this date, a PLA/ELA supplement was approved for filling, lyophilization, packaging, etc., by CLI

Date = 20000204; approval revoked from CLI and granted (reissued) to new owner, Aventis Pasteur Ltd.

Indications: [excerpt from "Indications and Usage” section of product insert/labeling, at time of 1991 approval]:

for pre-exposure immunization, in both primary series and periodic reinforcement, and for post-exposure prophylaxis against rabies

Status: The product no longer appears on recent CBER/FDA approval lists, indicating that it is no longer manufactured and its license has been voluntarily revoked.

Tech. transfer: The vaccine was originally developed by the Wistar Institute. See Wiktor, T.J., Plotkin, S.A., and Kop-rowski, H., “Development and clinical trials of the new human rabies vaccine of tissue culture (human diploid cell) origin,” Dev. Biol. Stand., 1978;40:3-9.

Trials: In pre-exposure/prophylaxis clinical trials since 1979 with this vaccine and less purified predecessor vaccines in over 600 subjects, all receiving three injections developed antibodies at a level of 1.0 IU/ml or greater.