Status: approved; marketed

Organizations involved:

Sanofi Pasteur S.A. – Manuf.; R&D; Tech.; Intl. mark.

Sanofi Pasteur Inc. – USA mark.

Wistar Institute – R&D; Tech.

Cross ref: See Rabies Vaccine Products (entry #525).

Description: Rabies Vaccine or Imovax is a lyophilized (freeze-dried) suspension of rabies virus (Pitman-Moore strain PM-1503-3M) cultured in MRC-5 human diploid cells inactivated with beta-propiolactone (BPL). Imovax is marketed in two different formulations, each with its own product insert/labeling – Imovax Rabies, for intramuscular administration and Imovax Rabies I.D., for intradermal administration (pre-exposure use only).

From 1973 to 1977 (prior to U.S. approval), Imovax was cultured in WI-38 cells (licensed from the Wistar Institute which developed this and the prior MRC-5 cultured vaccine, RABIE-VAX). MRC-5 human diploid cells have been used for cell culture of this vaccine since 1977. Antibody studies have shown the two vaccines to have comparable immunogenicity (and safety and efficacy has been demonstrated in clinical trials and by decades of use).

Imovax Rabies Vaccine (for intramuscular administration) is supplied in a tamper-proof plastic box containing a single-dose vial of lyophilized vaccine, a disposable syringe containing diluent for reconstitution, and a small needle for administration. Imovax Rabies I.D. (intradermal), apparently still approved but no longer marketed in the U.S., was supplied in a tamper-proof unit containing a disposable syringe with integral needle containing a single dose of lyophilized vaccine, and one vial of Sterile Water for Injection USP for reconstitution. Both vaccine formulations are stored at 2-8˚C (refrigerated). The potency of one dose (1.0 mL) of both Imovax Rabies Vaccine and Imovax Rabies I.D. is greater than or equal to 2.5 international units (IU) of rabies antigen. After reconstitution, Imovax Rabies (i.m.) contains less than 100 mg Albumin (Human), less than 150 µg neomycin sulfate (antibiotic used in culture media), and 20 µg of phenol red (pH indicator). The vaccine contains no preservatives or stabilizers.

Nomenclature: Rabies Vaccine/Sanofi France [BIO]; IMOVAX Rabies [TR]; Rabies Vaccine [FDA]; Rabies Vaccine, Human Diploid Cell (HDCV) [FDA former]; Wistar rabies virus strain PM-1503-3M [SY]; HDCV vaccine [SY]; human diploid cell rabies vaccine (HDCV) [SY]; Mérieux Imovax Rabies Vaccine [SY]; NDC 49281-250-10; NDC 49281-251-20 [NDC]

History: Drs. T. Wiktor, H. Koprowski, and S. Pltokin, Wistar Institute, and collaborators originally developed this cell culture-based vaccine using the WI-38 host cell line. MRC-5 cultured vaccine entered trials in 1971, received first approval in France in 1977 and U.S. approval in 1980.

Companies.: The vaccine is manufactured by Sanofi Pasteur S.A. (Lyon, France), CBER/FDA est. no. 0384, formerly Aventis Pasteur S.A. It is marketed in the U.S. by Sanofi Pasteur Inc., formerly Aventis Pasteur Inc., and internationally by Sanofi Pasteur S.A. affiliates. Aventis merged into Sanofi Aventis S.A. in late 2004.

Manufacture: The vaccine is manufactured from rabies virus Pitman-Moore strain PM-1503-3M, originally obtained from the Wistar Institute, cultured in human diploid MRC-5 cells. The virus is harvested from the cells, concentrated by ultrafiltration, and is inactivated using beta-propiolactone (BPL). The product is filtered, filled into 1.0 mL (one dose) vials, and freeze-dried (lyophilized). The approved (but not marketed in the U.S.) prefilled syringe packaging of the vaccine is filled with 0.1 mL of vaccine, and freeze-dried (lyophilized), flooded with nitrogen, and the syringes assembled and placed into glass tubes sealed with rubber stoppers and aluminum caps, all in the lyophilizer apparatus. Imovax is manufactured and tested using a process analogous to that used by Connaught Ltd. (now Sanofi Pasteur Ltd.) for manufacture of a predecessor vaccine, RABIE-VAX (see entry above).

Inactivated bulk vaccine is tested for mycoplasma and sterility, and for effective virus concentration by direct inoculation into mice and an amplification test in cell culture. The cell cultures used are derived from a frozen cell bank. The cell substrate for each production lot is tested for contamination in monkey kidney and human cell cultures for mycoplasma, sterility, and identity. The rabies virus seed lot is tested for contamination in human and monkey cell cultures, suckling and adult mice, and guinea pigs; and for cultivable and non-cultivable mycoplasma, sterility, and identity. The virus harvest (prior to inactivation) is tested for infectious titer, sterility, and mycoplasma. The inactivated bulk vaccine is also tested for mycoplasma, sterility, and for effective inactivation of rabies virus by direct inoculation into mice and amplification in cell cultures prior to mouse inoculation. The final lyophilized product is tested for moisture, protein content, sterility, potency, and general safety in guinea pigs and mice. Tests are performed in a manner consistent with 21 CFR Part 610 Subparts B and D, and as described in Laboratory Techniques in Rabies, edited by M.M. Kaplan and H. Koprowski, World Health Organization (WHO), Geneva, 1973.

FDA class: Biologic PLA

CBER class: Viral And Rickettsial Vaccines

Approvals: Date = 19800609; first approval, PLA/ELA ref. no. 79-340 and 79-359, for Imovax (intramuscular) granted to Institut Merieux, later Aventis Pasteur S.A.

Date = unknown; supplemental approval of current lower dose, intradermally administered product

Date = 20000204; license revoked from Pasteur Merieux Serum et Vaccins, S.A. and granted (reissued) to new owner, Aventis Pasteur S.A.

Indications: The "Indications and Usage Section” of the product insert/labeling (not shown) is 3 pages long and provides a detailed guide to use of the vaccine for both rabies prophylaxis and treatment.

Status: The vaccine is approved and used in most countries worldwide.

Tech. transfer: The Pitman-Moore strain PM-1503-3M of rabies virus originated from the Wistar Institute.

Market: The 2007 Average Wholesale Price (AWP) is $188.10/vial, with a Direct Price (Manufacturer’s discount price) of $156.75 (Red Book, 2007).

The Sanofi Pasteur list price (Jan. 2006) is $156.75/vial for 1-9 one-dose vials ($132.33/dose; $132.33 in 2004), and $153.20/vial for 10-49 vials ($129.34 in 2004).

In its March 2006 price list, FFF Enterprises, a major biologics distributor, reported $147.58/vial (same in March 2005 and 2004).