Rabies Vaccine, Inactivated - RabAvert
Status: approved; marketed
Organizations involved:
Novartis Vaccines and Diagnostics Ltd. – Manuf.; R&D; Tech.; World mark.
Novartis AG – Parent
General Injectables & Vaccines Inc. – USA mark.
Chiron Behring GmbH & Co. KG – Former
Chiron Corp. – Parent; Former
Behringwerke AG – Former
Cross ref: See the Rabies Vaccine Products entry.
Description: RabAvert is a lyophilized (freeze-dried) formulation of inactivated rabies virus vaccine obtained from culture of the Flury LEP (Low Egg Passage) C25 rabies virus strain in primary cultures of chicken embryo (PCEC) fibroblasts using a synthetic culture medium with the addition of human albumin, polygeline (processed bovine gelatin), and antibiotics. The PCEC cultured virus is inactivated with beta-propio-lactone (BPL), with purification including sucrose density-gradient zonal centrifugation.
RabAvert is packaged in a single-dose vial for reconstitution with the accompanying diluent to a final volume of 1.0 mL just before intramuscular administration. A single 1 mL dose contains at least 2.5 IU of rabies antigen as determined by the NIH mouse potency test using the U.S. reference standard, less than 12 mg polygeline, 1 mg potassium glutamate, 0.3 mg sodium EDTA, and 0.3 µg of Albumin (Human). Neomycin is present at < 1 ng, chlortetracycline at < 20 ng, and am-pho-tericin B at < 2 ng per dose. Minimal amounts of chicken protein may be present in the final product; ovalbumin content is less than 3 ng/dose (1 mL), based on ELISA.
RabAvert has a shelf life of four years (originally 3), longer than any other rabies vaccine available in the U.S., when stored at 2-8°C (36-46°F; refrigerated).
Nomenclature: Rabies Vaccine/Chiron [BIO]; RabAvert [TR]; Rabies Vaccine [SY]; Purified Chick Embryo Cell Vaccine (PCEC) [SY]; PCEC [SY]; RabiPur [TR in Europe]
Companies.: RabAvert is manufactured by Chiron Behring GmbH & Co. (Marburg, Germany); CBER/FDA est. no. 1222, formerly a subsidiary of Chiron Corp.; merged into Novartis Vaccines and Diagnostics Ltd., Novartis AG in Oct. 2005. RabAvert is distributed in the U.S. by General Injectables & Vaccines Inc. (GIV), with marketing support from Novartis.
The vaccine was originally developed by Behring-werke AG, a subsidiary of Hoechst Marion Roussel (HMR), later Chiron Behring GmbH & Co., a joint venture between Chiron Corp. and HMR, later fully owned by Chiron, now part of Novartis AG.
Manufacture: RabAvert is manufactured by culturing the rabies fixed-virus strain Flury LEP in primary cultures of chicken embryo (egg) fibroblasts. The strain Flury LEP was originally obtained from American Type Culture Collection (ATCC) as the 59th egg passage. The culture medium is a synthetic cell culture medium with the addition of human albumin, polygeline (processed bovine gelatin), and antibiotics. The cultured virus is inactivated with beta-propiolactone (BPL). Treatment with BPL induces a chemical modification, forming OH-propionic groups. The inactivated virus is purified, including zonal centrifugation in a sucrose density--gradient. The vaccine is filled in vials and lyophilized after addition of a stabilizer solution (buffered polygeline and potassium glutamate).
The vaccine’s manufacturing process includes improved removal of human albumin, which is associated with hypersensitivity reactions in some patients and a theoretical risk of infection with human viruses and other pathogens.
Chick-embryos (fertile eggs) are the source for the fibroblast cells. These are cheap, readily available, and the yield of cells is very good. For vaccine manufacture, only specific pathogen-free (SPF) eggs are used, i.e., eggs of chickens raised free from specific pathogens on dedicated chicken farms. Testing of the product’s components and excipients using currently available methods has not detected any adventitious agents. Bovine components originate only from source countries known to be free of bovine spongiform encephalopathy (BSE). The potency of the final product is determined by the NIH mouse potency test using the U.S. reference standard.
FDA class: Biologic PLA
CBER class: Viral And Rickettsial Vaccines
Approvals: Date = 19971020; first approval, PLA
Indications: [portion of the "Indications and Usage” section from the product insert/labeling];
RabAvert is indicated for pre-exposure immunization, in both primary series and booster dose, and for post-exposure prophylaxis against rabies. Pre-exposure immunization consists of three doses of RabAvert 1.0 mL, intramuscularly (deltoid region), one each on days 0, 7, and 21 or 28. A complete course of post-exposure immunization for previously unvaccinated adults and children consists of a total of 5 doses, each 1.0 mL: one IM injection on each of days 0, 3, 7, 14 and 28.
Status: The PLA was submitted on Sept. 8, 1989, and approved on Oct. 20, 1997; review time = ~97.2 months or ~8.1 years. RabAvert was launched in the U.S. on Oct. 21, 1997. Upon approval, RabAvert was the first rabies vaccine to be introduced in the U.S. for nearly ten years.
This vaccine has long been on the market in many European and other countries worldwide. Its first approvals were in Germany and Thailand in 1985. More than 19 million doses have administered since 1985.
In Jan. 2008, FDA notified Novartis AG that its German plant had produced contaminated vaccines, and it hadfailed to track down the source of the problems. FDA found significant deviations from GMP at the plant, which make also makes diphtheria and tetanus concentrates. This situation was subsequently resolved.
Tech. transfer: U.S. patent 4,115,195, “Rabies vaccine preparation,” Sept. 19, 1978, assigned to Behring-werke AG, describes use of chick-embryo fibroblast cell culture for manufacture of inactivated rabies vaccines. The patent covers adaptation of the virus to the cell line. Chiron assumed assignment of this patent through its former Chiron Behring GmbH & Co. KG vaccines joint venture with Hoechst AG.
Trials: The immunogenicity of RabAvert given as a primary series for pre-exposure prophylaxis has been demonstrated in trials worldwide, including trials in the U.S., U.K., Croatia, and Thailand. The vaccine is considered highly, even 100%, effective. Unlike nerve tissue-derived vaccines used widely in the U.S. before the introduction of cell culture vaccines and still used in many lesser-developed countries, neurological complications with cell culture vaccines are rare.
Medical: A complete course of post-exposure immunization in previously unvaccinated adults and children involves a total of five doses on days 0, 3, 7, 14 and 28. Rabies immune globulin may also be co-administered for post-exposure prophylaxis. Pre-exposure prophylactic vaccination involves 1 mL injected on days 0, 7, 21 or 28. The vaccine is to be administered only by intramuscular injection, usually into the deltoid region (upper arm) or the thigh of young children.
RabAvert results in rabies antibody titers above the minimally protective level of 0.5 IU/ml within 14 days after initiating the immunization series.
Market: The 2007 Average Wholesale Price (AWP) is $198.00/vial (Red Book, 2007).
RabAvert is marketed in about 30 or more countries.
Companies involvement:
Full monograph
529 Rabies Vaccine/Novartis
Nomenclature:
Rabies Vaccine/Novartis [BIO]
RabAvert [TR]
PCEC [SY]
Purified Chick Embryo Cell Vaccine (PCEC) [SY]
Rabies Vaccine [SY]
RabiPur [TR in Europe]
FDA Class: Biologic PLA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19971020
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
chicken source materials
human materials used<!-- humansource -->
vaccines, inactivated
vaccines, viral
amphotericin B
chicken embryo (egg) culture
chlortetracycline
Flury LEP (Low Egg Passage) C25, rabies virus
mammalian cell culture
neomycin
rabies virus strain Flury LEP (Low Egg Passage) C25
Albumin (Human)
beta-propiolactone (BPL; beta propiolactone)
beta-propiolactone (BPL; beta propiolactone)
chicken proteins
gelatin (bovine source)
lyophilized (freeze-dried)
NIH mouse potency test
polygeline
potassium glutamate
Sterile Water for Injection
sucrose
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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