Status: marketed in Europe

Organizations involved:

Merck & Co., Inc. – Manuf.; R&D; Tech.

Sanofi Pasteur MSD – Europe mark.

Sanofi Aventis S.A. – Parent

Biogen Idec, Inc. — Tech.

Chiron Corp. — Tech.

Novartis AG – Parent

Washington Research Foundation — Tech.

University of Washington – Tech.

University of California – Tech.

Cross ref.: See the entries for Hepatitis B Virus Vaccine Products; and Hepatitis B Vaccine, rDNA/Merck (Recombivax HB), which contains the same recombinant antigen.

Description: HBVAXPRO is an aqueous formulation of recombinant hepatitis B virus surface antigen (HBsAg) vaccine expressed by a transformed Saccharomyces cerevisiae (yeast) cell line (strain 2150-2-3), inactivated with formalin/formaldehyde, and adsorbed on aluminum potassium sulfate (alum) adjuvant. The vaccine is thimerosal (mercury-based preservative)-free, i.e., manufactured and formulated without addition of thimerosal. The recombinant HBsAg in this vaccine is the same as also manufactured by Merck for use in Recombivax HB (and combination vaccines containing this component), but Recombivax HB is formulated with aluminum hydroxide adjuvant.

HBVAXPRO is packaged in vials and prefilled syringes with different doses and concentrations - 5 µg/0.5 mL, 10 µg/1.0 and 40 µg/mL - for delivery of 5 µg/0.5 mL, 10 µg/1.0 mL, and 40 µg/mL. The shelf life is three years when stored at 2-8˚C (refrigerated). Excipients in the vaccine are sodium chloride, borax and Water for Injection.

Nomenclature: Hepatitis B vaccine, rDNA/HBVAXPRO [BIO]; HBVAXPRO [TR]; Hepatitis B (Recombinant) vaccine [INN]; hepatitis B virus (HBV) subtype adw surface antigen (rHBsAg) p24 nonglycosylated lipoprotein complex [SY]; HBsAg, rDNA [SY]

Companies.: HBVAXPRO is manufactured (according to EMEA/EU disclosures) by a European subsidiary of Merck & Co., Inc. in Haarlem, The Netherlands (which imports bulk rHBsAg from Merck in the U.S.), and is marketed in Europe by Sanofi Pasteur MSD, a joint venture of Sanofi Aventis S.A. (formerly Aventis Pasteur S.A.) and Merck & Co., Inc.

Manufacture: Each yeast fermentation process yields ~2,100 L of final culture. Yeast cells are concentrated and diafiltered to produce a ~40% cell suspension. Purification involves two phases, with Phase 1 from cell lysate to Concentrated Silica Product (CSP), and Phase 2 from CSP to Sterile Filtered Product (SFP). Formulation involves two phases, with Formaldehyde Treatment from SFP to Final Aqueous Product (FAF) and Alum Co-precipitation from FAP to Bulk Alum Product (BAP). Testing on each lot of final product includes sterility, fill volume, LAL, identity, In Vitro Relative Potency, aluminum, pH, and sodium chloride.

HBVAXPRO is manufactured from the same intermediate, thimerosal-free 40 µg Bulk Alum Product, previously licensed and used in preservative-free PROCOMVAX and HEXAVAC (European combination vaccines), with this diluted to obtain rHBsAg for the final products (5 µg/0.5 mL and 10 µg/1.0 formulations) or used undiluted for the 40 µg/mL product. [Information in this section primarily from the European Product Assessment Report (EPAR)].

Indications: [European Union]: “Active immunization against Hepatitis B virus infection caused by all known subtypes in all age groups considered at risk of exposure to Hepatitis B”

Status: EMEA/European Union was granted on April 27, 2001. This thimerosal-free vaccine is particularly targeted for use in infants from birth through age 15. The impetus for development of this thimerosal-free formulation was the July 1999 EMEA/EU public statement (EMEA/20962/99) recommending the promotion of vaccines without thimerosal. Clinical studies with HBVAXPRO without thimerosal were not submitted, and approval was based on the prior thimerosal-containing (1:20,000) product marketed in European countries by Sanofi Pasteur MSD. In this respect, the thimerosal formulation HBVAXPRO has many characteristics of a biogeneric, biosimilar, biocomparable, follow-on, or other type of generic biopharmaceutical.

Medical: Two primary vaccination regimens are approved for use in children and adolescents, an accelerated schedule with injections at 0, 1 and 6 months, resulting in quicker generation of antibodies; and a routine schedule at 0, 1, 2 and 12 months.

Tech. transfer: See the Tech. transfer sections of the Hepatitis B Virus Vaccine Products and Hepatitis B Vaccine, rDNA/Merck (Recombivax HB) entries. Note, only a few of the major technology/licensing sources ( Biogen, Chiron, University of California, and Washington Research Foundation) are indexed for this entry..

Market: The author has included HBVAXPRO sales in with his estimate of Recombivax HB sales.