Status: approved; marketed

Organizations involved:

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

Sanofi Pasteur Inc. – USA mark.

Cross ref: See the Polio Vaccine Products entry above. See also the entry (#519) for another inactivated poliovirus vaccine from Sanofi Pasteur approved but not marketed in the U.S. – Poliovirus Vaccine Inactivated (Human Diploid Cell).

Description: Poliovirus Vaccine Inactivated or IPOL is an aqueous suspension of three inactivated strains of poliovirus – Type 1 (Mahoney), Type 2 (MEF-1) and Type 3 (Saukett) – cultured in Vero cells, a continuous African green monkey kidney cell line, using micro-carrier culture methods. The viruses are concentrated, purified, and made noninfectious by inactivation with formalin (formaldehyde in aqueous solution). IPOL is essentially inactivated virus concentrates in M-199 culture medium.

The vaccine is packaged in 10-dose vials. Each dose (0.5 mL) of trivalent vaccine is formulated to contain 40D antigen units of Type 1 poliovirus, 8D antigen units of Type 2 poliovirus, and 32D antigen units of Type 3 poliovirus, determined by comparison to reference preparations. The inactivated viruses are dissolved in phosphate buffered saline. Also present are 0.5% of 2-phenoxyethanol and a maximum of 0.02% of formaldehyde per dose as antimicrobial preservatives. Neomycin, streptomycin, and polymyxin B are used in vaccine cell culture, and amounts below the limits of detection may be present (less than 5 ng neo-mycin, 200 ng streptomycin, and 25 ng polymyxin B per dose). Residual calf serum protein in the vaccine from the culture medium is less than 1 ppm. The vaccine is clear and colorless, and is administered intramuscularly or subcutaneously. IPOL is stored at 2-8˚C (refrigerated).

The culture methods and improvements in purification, concentration, and standardization of poliovirus antigen used for manufacture of this current IPOL vaccine yields a more potent and consistently immunogenic vaccine than the inactivated poliovirus vaccine (#519) previously manufactured by Connaught Labs., Ltd. (Canada; now Sanofi Pasteur Ltd.) and marketed in the U.S. prior to 1988.

Nomenclature: Poliovirus Vaccine (IPOL) [BIO]; IPOL [TR]; Poliovirus Vaccine Inactivated (Monkey Kidney Cell) [FDA]; enhanced, inactivated polio vaccine [SY]; eIPV [SY]; IPV [CDC]; NDC 49281-860-51; 49281-860-52; 49281-860-10 [NDC]

Companies.: IPOL 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., and internationally by Sanofi Pasteur S.A. affiliates. Aventis merged into Sanofi Aventis S.A. in late 2004.

In spring 2007, it was reported that Sanofi Pasteur is investing €200m in expanding manufacturing capacity at its Val de Reuil, France, facility that includes manufacture of polio vaccines.

Manufacture: The continuous African green monkey kidney Vero cell line used for cell culture is distributed by the American Type Culture Collection under no. ATCC-CCL 81. This cell line is at its 124th passage. Anchorage-dependent cells, e.g., Vero cells, are difficult to culture in liquid media. Microcarrier culture involves use of culture medium-suspended microscopic dextran beads to which these cells attach, allowing large-scale culture of cells at high concentrations.

The three virus strains are independently grown in cultures of Vero cells using the microcarrier technique. The cells are first grown in Eagle Minimal Essential Medium (MEM) supplemented with newborn calf serum and tested for adventitious agents prior to use. For large-scale culture, the culture medium is replaced by Medium M-199, without calf serum. After clarification and filtration, viral suspensions are concentrated by ultrafiltration, and purified by three liquid chromatography steps using anion exchange, gel filtration, and anion exchange columns. After re-equilibration of the purified viral suspension with Medium M-199 and adjustment of the antigen titer, the monovalent viral suspensions are inactivated by incubation at 37˚C for at least 12 days with 1:4000 formalin (formaldehyde gas in solution). The inactivated viruses are pooled and the vaccine formulated. For each lot, D-antigen content is determined using the D-antigen ELISA assay, and immunogenicity is determined by in vivo testing in animals.

FDA class: Biologic PLA

CBER class: Viral And Rickettsial Vaccines

Approvals: Date = 19630124; first approval of a different Poliovirus Vaccine Inactivated (Monkey Kidney Cell) manufactured by Connaught Labs., Ltd. (Canada); approval was revoked on Nov. 20, 1987

Date = 19901221; first approval (PLA) for current IPOL vaccine manufactured in France; according to CBER/FDA

Date = 19970320; supplemental approval for routine vaccination as part of an all IPV regimen

Date = 20000317; license revoked from Pasteur Merieux Serum et Vaccins, S.A. and granted (reissued) to new owner, Aventis Pasteur S.A.

Indications: [portion of the "INDICATIONS AND USAGE” section of product insert/labeling]:

IPOL is indicated for active immunization of infants (as young as 6 weeks of age), children and adults for the prevention of poliomyelitis caused by poliovirus Types 1, 2, and 3.

Status: This IPOL vaccine manufactured by Sanofi Aventis S.A. in France is currently marketed in the U.S. IPOL is also approved and marketed in many other countries, primarily developed countries, while OPV is used as the primary vaccine in lesser-developed countries.

A comparable inactivated poliovirus vaccine from Connaught Labs., Ltd. (Canada), now Sanofi Pasteur Ltd., was formerly approved in the U.S. from Jan. 24, 1963 to Nov. 20, 1987.

The regulatory status of the original approval for the current vaccine, in terms of whether it received an original PLA/ELA or a sup-ple-mental PLA/ELA, is not clear, due to conflicting FDA documentation.

In Dec. 2000, CBER/FDA reported that IPOL was being manufactured using bovine-derived material of unknown/undocumented origin, possibly from countries on the official USDA list of countries known to have cattle with BSE. Aventis Pasteur resolved this situation. See the Vaccine Products entry (#400) for information about BSE/TSE.

See the Code of Federal Regulations (CFR) Title 21 Part 630, Sec. 630.1, “Poliovirus Vaccine Inactivated,” for further information about IPOL/IPV-type vaccines.

Trials: Studies with infants and children have shown the vaccine produces high levels of neutralizing antibodies for all three types of poliovirus in over 99% of vaccinees after two doses. Field studies in Europe with a similar inactivated poliovirus vaccine indicate the persistence of circulating antibodies for at least 10 years. A direct relationship exists between the antigenic content of the vaccine, the frequency of sero-conversion, and resulting antibody titer.

Medical: The recommended primary series is two 0.5 mL sub-cutaneous injections at a 1-2 month interval, followed by a booster dose (0.5 mL) 6-12 months later. Previously vaccinated persons at increased risk may receive a single dose as a booster. Completion of a primary series of poliovirus vaccination is generally required in all states, e.g., prior to entry of children into school.

Market: With recent recommendations for use of inactivated (IPV) rather than oral live (OPV) vaccines, nearly all U.S sales and an ever increasing proportion of polio vaccine use worldwide, particularly in developed countries, now involve inactivated vaccines. IPV has substantially replaced use of live oral polio vaccine (OPV) in all but lesser-developed countries. This IPOL vaccine is now the only IPV and the primary poliovirus vaccine used in the U.S.

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 $25.91/10-dose vial ($22.80/dose in 2006; $21.80 in 2005); and $26.30/pack of 10 prefilled 1-dose syringes (26.34 in 2006). The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $11.06 for 10-dose vials and packs of 10 prefilled 1-dose syringes ($10.82/dose in 2006; $10.42 in 2005). These prices include the $3.00/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. Sanofi Pasteur’s contract with NIP, CDC, expires on March 31, 2008.

The 2007 Average Wholesale Price (AWP) is $314.58/10 single-dose vials, with a Direct Price (Manufacturer’s discount price) of $263.40; and $273.55/10-dose vial, with a Direct Price of $227.96 (Red Book, 2007). These prices include $.75/dose ($.75/covered component vaccine) federal excise tax charged by the manufacturer for the federal vaccine liability insurance program.

The Sanofi Pasteur list price (Jan. 2006) is $220.46/10-dose vial ($210.46 in 2004 and 2003), and $255.90/10 prefilled syringes. This includes the $.75/dose federal excise tax.

In its March 30, 2004 price list, FFF Enterprises, a major biologics distributor, reported $237.45/5 mL 10-dose vial (same in 2005; $242.73 in 2004). In March 2004, FFF reported $282.11/package of ten 0.5 mL prefilled syringes (same in 2005). This includes the $.75/dose federal excise tax.

Aventis Pasteur reported $118 million worldwide sales of inactivated poliovirus vaccines in 1999. In 1997, 5.23 million net doses of IPV were distributed in the U.S.