Status: approved; marketed

Organizations involved:

Sanofi Pasteur Inc. – Manuf.; R&D; Tech.; USA mark.

Sanofi Pasteur S.A. – Parent

Cross ref: See Influenza Virus Vaccines (entry #470).

Description: Influenza Virus Vaccine USP, (Zonal Purified, Subvirion) or Fluzone is a conventional trivalent inactivated split (subvirion) injectable influenza virus vaccine. Fluzone, like other U.S. vaccines, is standardized according to federal requirements to contain 45 µg hemagglutinin (HA) per 0.5 mL dose, in the 1recommended ratio of 15 g HA from each of the three influenza virus strains used in each year’s vaccine. Gelatin (bovine source) 0.05% is added as a stabilizer and thimerosal (mercury derivative; see #939) 1:10,000 is generally added as an antimicrobial preservative to vaccine packaged in multi-dose vials. Thimerosal formulations contain 25 µg mercury/0.5 mL dose. A preservative- (thimerosal)-free formulation was first approved in 2002. The “thimerosal-free” formulation contains a trace amount of residual thimerosal (≤ 0.5 µg Hg/0.25 mL dose; ≤ 1.0 µg Hg/0.5 mL dose) from the manufacturing process. No antibiotics are used in the manufacture of Fluzone. A relatively new “No Preservative” formulation contains no thimerosal, i.e., it is not used at all in the manufacturing process.

Fluzone vaccine is packaged in four different presentations: a 5 mL vial which containng thimerosal [(mercury derivative), (25 g mercury/dose)]; a 0.25 mL prefilled syringe (No Preservative: Pediatric Dose, for 6 – 35 months of age) distinguished by a pink syringe plunger rod; a 0.5 mL prefilled syringe (No Preservative, for 36 months of age and older); and a 0.5 mL vial (No Preservative, for 36 months of age and older). There is no thimerosal used in the manufacturing process of the No Preservative unit dose presentations of Fluzone vaccine. The new No Preservative formulation became available in 2005 in single-dose, prefilled syringes in both a pediatric dose package (Fluzone, Influenza Virus Vaccine, No Preservative: Pediatric Dose) and a standard dose package (Fluzone, Influenza Virus Vaccine, No Preservative) for children ages three years and above. The pediatric dose package contains 0.25 mL of vaccine and the standard dose package contains 0.50 mL. Fluzone, after shaking syringe/vial well, is essentially clear and slightly opalescent in color.

Nomenclature: Influenza Vaccine/Sanofi [BIO]; FLUZONE [TR]; Fluzone, Influenza Virus Vaccine, No Preservative [TR trade name of new zero thimerosal formulation]; Vaxigrip [TR ex-US]; Influenza virus vaccine [FDA USAN]; Influenza Virus Vaccine USP Trivalent Types A and B (Zonal Purified, Subvirion) [FDA on adult dose insert/labeling]; Influenza Virus Vaccine USP [USP]; NDC 49281-369-25; 49281-370-11; 49281-370-15; and 49281-369-50 [NDC]

Companies.: Fluzone was developed and is manufactured by Sanofi Pasteur Inc. (previously Aventis Pasteur Inc., Pasteur Merieux Connaught Inc., and Connaught Inc.), CBER/FDA est. no. 1277. These facilities provide about half of the U.S. supply of influenza vaccine. Sanofi Pasteur S.A., the parent company, globally produces more than half the influenza vaccine used worldwide. Aventis merged into Sanofi Aventis S.A. in late 2004. Fluzone is presumed to be only or primarily distributed in the U.S.

Aventis Pasteur/Sanofi Aventis is expanding its production capacity as demand increases (and as other manufacturers, e.g., Wyeth, have left the market). In 2001, Aventis Pasteur expanded its U.S. influenza vaccine production capacity by 20%. In late 2002, the company announced an $80 million investment to increase filling and formulation capacity at its Swiftwater, PA, facility. In 2002, the company shipped almost 44 million doses by the end of October, representing the largest volume ever supplied by one manufacturer to the U.S. market by that date. To ensure sufficient supply in for the 2003/2004 flu season, Aventis Pasteur further increased production capacity.

To further address the longer-term U.S. needs, in 2005, Sanofi Pasteur began construction a new $160 million, 140,000 sq. ft. bulk influenza vaccine manufacturing facility [the New Influenza Vaccine Manufacturing Facility (NIVMF), Building (b)(4) ] at its Swiftwater, PA, facility to produce seasonal influenza vaccine for both routine influenza immunization and also vaccine in case of an influenza pandemic. The new facility was expected to come online for the 2008-2009 influenza season. The company manufactured about 50 million doses for the U.S. market for the 2006/7 flu season. Since 2003, Sanofi Pasteur’s global manufacturing capacity for the influenza vaccine has increased by more than 40%, and sales of the vaccines have more than tripled since 1995. The new manufacturing facility was approved by FDA in April 2009, well in time for manufacture of 2009/2010 seasonal vaccine. The new plant now has the capacity to manufacture 100 million doses of Fluzone, with Sanofi-Pasteur having total manufacturing capacity of 150 million doses/year.

Manufacture: Influenza virus is harvested from embryonated chicken embryos (eggs), inactivated with form-aldehyde, virus is concentrated and purified in a linear sucrose density gradient solution using a continuous flow centrifuge, isolated whole virus particles virus are chemically disrupted (inactivated) using polyethylene glycol p-isooctylphenyl ether (octoxynol; octyl phenyl-polyethylene glycol ether; Triton X-100 from Rohm and Haas, Co.), and the resulting split hemagglutinin (HA) and neuraminidase (NA) surface antigens (split virus) are further purified by chemical means and suspended in sodium phosphate-buffered isotonic sodium chloride solution. Purified NA and HA are later combined. See also the Manufacturing and Tech. transfer sections of the Influenza Virus Vaccines entry (#470).

FDA class: Biologic PLA

CBER class: Viral And Rickettsial Vaccines

Approvals: Date = 19470916; first approval for an Influenza Virus Vaccine (whole, not subvirion), granted to Merrell-National Labs., Richardson-Merrell Inc.

Date = 19780103; licenses (PLA/ELA) revoked and granted (reissued) to the new owner, Connaught Labs., Inc. (CLI)

Date = 19991209; PLA revoked and granted (reissued) to new owner, Aventis Pasteur Inc.

Date = 20020904; BLA supplement; Indication = approval of a preservative free formulation in single dose 0.25 ml syringes for pediatric use and 0.5 ml -syringes for adults and children

Date = 20041223; BLA supplement; Indication = new single-dose formulation without thimerosal for the 0.25 mL and 0.5 mL syringes

Date = 20050309; BLA supplement; Indication = approval of a “No preservative” formulation containing no thimerosal; the only influenza vaccine explicitly approved for use in children 6 to 35 months of age

Date = 20050714; BLA supplement; Indication = approval of a preservative-free (thimersal traces) single dose presentation in a unit dose vial

Date = 20090506; BLA supplement (STN: BL 103914/5232); Indication = approval of new manufacturing facility [the New Influenza Vaccine Manufacturing Facility (NIVMF), Building (b)(4)] in Swiftwater, PA, for the production of seasonal influenza vaccine (which could also be used for H1N1 influenza strain vaccine

Indications: [First sentence of the "INDICATIONS AND USAGE” section of product insert/labeling; from 2005-2006 flu season; The considerable unshown text discusses in detail recommendations for vaccination of various groups]:

Fluzone vaccine is indicated for active immunization against influenza disease caused by influenza virus types A and B contained in the vaccine in subjects from 6 months of age and older...[truncated].

Status: The newly licensed “No Preservative” formulation for immunization of infants aged 6 to 35 months is replacing the previously licensed “preservative-free” Fluzone pediatric formulation, which contained trace amounts of thimerosal. Sanofi Pasteur planned to manufacture ~8 million doses of the new formulation for the 2005-06 influenza season. This was almost double the number of pediatric doses of influenza vaccine than was supplied in the 2004-2005 season.

The company also has marketed a whole (not sub-virion or split) version of Fluzone - Influenza Virus Vaccine USP Trivalent Types A and B (Zonal Purified, Whole Virion). The lack availability of a product insert/labeling for this product for the 2000/1, 2002/3 and later flu seasons indicates this is no longer manufactured.

Tech. transfer: Related patents include U.S. patent 4,327,182, “Purification of influenza sub-unit vaccine” April 27, 1982 (now expired), assigned to Connaught Labs. Inc. See the Tech. transfer section of the Influenza Virus Vaccines entry (#470) which discusses this as an exemplary method for manufacture of split or subvirion influenza virus vaccines.

Market: See also the Influenza Vaccine Products entry above for further market and supply information. Fluzone generally holds a ≥50% share of the U.S. market for influenza vaccines.

Total worldwide sales were $1.152 bilion in 2012 and $1.052 billion in 2011 (for all Fluzone products, i.v. and i.d.)

Sanofi Pasteur reports that it produces approximately 40% of the influenza vaccines distributed worldwide. It was responsible for over 45% of the vaccines distributed in the U.S. during the 2008/2009 influenza season..

Fluzone from Sanofi Pasteur is the largest-selling influenza vaccine in the U.S., with 40% the U.S. market.

Prior to is new 100 million unit capacity plant coming online in early 2009, Sanofi Pasteur shipped about 50 million doses/year in recent years.

The 2007 Average Wholesale Price (AWP) is $161.86 for 10 pediatric (0.25 mL) thimerosal-containing single-dose vials (presumably thimerosal-free/reduced), with a Direct Price (Manufacturer’s discount) of $136.13; $132.88/adult 10-dose vial (presumably thimerosal-preserved); and $174.46 for 10 single-dose vials (presumably thimerosal-free/reduced), with a Direct Price of $146.63. These prices include the $0.75/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program.

As reported by the National Immunization Program (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the Private Sector Cost/Dose (average cost) per dose is $11.72/dose for thimerosal-containing 10-dose vials of Fluzone (age 6 months and older); $14.26/dose for preservative-free pediatric-dose (age 6-35 months) packs of 10 prefilled syringes; and $15.36/dose for “No-Preservative” (age 36 months and older) packs of 10 prefilled syringes. The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is is $10.153/dose for thimerosal-containing 10-dose vials of Fluzone (age 6 months and older); $12.77/dose for preservative-free pediatric-dose (age 6-35 months) packs of 10 prefilled syringes; and $13.751/dose for “No-Preservative” (age 36 months and older) packs of 10 prefilled syringes.. These prices include the $0.75/dose Federal Excise Tax charged by the manufacturer. Sanofi Pasteur’s contract with NIP, CDC, expires on Feb. 28, 2008.

Fluzone is the market leader in the U.S., comprising ≥50% of vaccine sold/used in each recent year.