Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed - Tripedia
Status: approved; marketed
Organizations involved:
Sanofi Pasteur Inc. – Manuf.; USA mark.
Sanofi Pasteur S.A. – Intl. mark.; Parent
Research Foundation for Microbial Diseases (BIKEN) – Manuf. other
Cross ref: See the entries for Pertussis Vaccine Products (#505); Pertussis Vaccines, Acellular (#506); Diphtheria and Pertussis Toxoids and Pertussis Vaccine (DTP/DTaP) Products (#429), and the entry for the other DTaP vaccine, Daptacel (#430), also manufactured by Sanofi Pasteur. See also entries for the diphtheria and tetanus toxoid components from Sanofi Pasteur; and the acellular pertussis toxoid component, Acellular Pertussis Vaccine Concentrate (For Further Manufacturing Use) (#507), from BIKEN. See also TriHIBit (#443), of which this DTaP vaccine is a component; Tetanus Toxoid Vaccines (#543); and Diphtheria Toxoid Products (#418).
Description: Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed or Tripedia is an aqueous formulation combining toxoids (inactivated toxins) from independent culture of Corynebacterium diphtheriae (diphtheria toxoid) and Clostridium tetani (tetanus toxoid), plus an acellular pertussis vaccine manufactured from culture of Bordetella pertussis bacteria by the Research Foundation for Microbial Diseases of Osaka University (BIKEN). The pertussis vaccine component contains formaldehyde-inactivated pertussis toxin (PT) and filamentous hemagglutinin (FHA) antigens. Both the diphtheria and tetanus toxoid components are adsorbed using aluminum potassium sulfate (alum) adjuvant.
Tripedia is packaged in single- and 15-dose vials. Each 0.5 mL dose contains 6.7 Lf units of diphtheria toxoid, 5 Lf units of tetanus toxoid, and 7.5 µg of pertussis antigens, expressed as protein nitrogen, in an isotonic phosphate-buffered saline solution containing sodium phosphate to control pH.
The original Tripedia formulation included addition of thimerosal, a mercury derivative (see #939), as an antimicrobial preservative at a concentration of 1:10,000. The current formulation is “preservative-free,” containing a only a trace (≤ 0.3 µg) of mercury residual from the manufacturing process (e.g., use in culture media components). Each 0.5 mL dose also contains, by assay, not more than 0.170 mg of aluminum and not more than 100 µg (0.02%) of residual formaldehyde.
Both diphtheria and tetanus toxoids induce at least 2 units of antibodies (antitoxin) per mL in the guinea pig potency test. Each dose contains 46.8 µg of pertussis antigens, represented in the final vaccine as approximately 23.4 µg of inactivated PT and 23.4 µg of FHA. The potency of the pertussis components is evaluated by measuring the antibody response to PT and FHA in immunized mice using an ELISA system. The inactivated acellular pertussis component contributes not more than 50 endotoxin units (EU) to the endotoxin content of 1 mL of DTaP. The vaccine contains unspecified amounts of gelatin (presumed bovine source) and polysorbate 80 (Tween 80) used during manufacture. The dating period is 30 months from the date of manufacture when stored at 2-8˚C (refrigerated). This includes one year in manufacturer’s cold storage, plus an additional 18 months. The date of manufacture is the date of the initiation of the earliest valid potency test of any component.
A new formulation of Tripedia without thimerosal preservative and containing a substantially reduced level of thimerosal was approved on March 7, 2001. This formulation contains only 0.5 µg of mercury per dose, a 95% reduction compared to the original formulation.
Nomenclature: DTaP Vaccine/Sanofi USA [BIO]; Tripedia [TR]; Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed [FDA]; DTaP Vaccine [SY]; DTPa [CDC]; NDC 49281-288-05; NDC 49281-288-15; NDC 49281-557-10; NDC 49281-288-05 [NDC]
Companies.: Tripedia and its diphtheria and tetanus toxoid components are manufactured by Sanofi Pasteur Inc. (Swift-water, PA), CBER/FDA est. no. 0711, formerly Aventis Pasteur Inc. Aventis merged into Sanofi Aventis S.A. in late 2004. Tripedia is marketed in the U.S. by Sanofi Pasteur Inc., and perhaps internationally by Sanofi Pasteur affiliates. An equivalent vaccine is marketed in Japan by Kaketsuken, formerly the Chemo-Sero-Therapeutic Research Institute.
Acellular Pertussis Vaccine (For Further Manufacturing Use) is manufactured by the Research Foundation for Microbial Diseases of Osaka University (BIKEN) under a shared manufacturing agreement. See #507.
Manufacture: The Acellular Pertussis Vaccine Concentrate (For Further Manufacturing Use) produced by The Research Foundation for Microbial Diseases of Osaka University (BIKEN) is combined with previously aluminum hydroxide-adsorbed diphtheria and tetanus toxoid pools manufactured by Sanofi Pasteur Inc., and diluted to a final volume using sterile phosphate-buffered physiological saline, to form Tripedia. Thimerosal previously was added as a preservative.
The acellular pertussis component is isolated from culture fluids of Phase 1 Bordetella pertussis grown in a modified Stainer-Scholte medium. After purification by salt precipitation, ultra-centrifugation, and ultrafiltration, preparations containing varying amounts of both pertussis toxin (PT) and filamentous hemagglutinin (FHA) are combined to obtain a 1:1 ratio and treated with formaldehyde to inactivate PT.
Cory-ne-bacterium diphtheriae cultures are grown in a modified Mueller and Miller medium. Clostridium tetani cultures are grown in a peptone-based medium. The purified bacterial toxins are detoxified with formaldehyde. The detoxified materials are then separately purified by serial ammonium sulfate fractionation and diafil-tration. The toxoids are adsorbed using aluminum potassium sulfate (alum). manufacture of a each lot of the Tetanus Toxoid Adsorbed component has been reported to require 11 months.
The finished product is tested for diphtheria toxoid and tetanus toxoid potency in guinea pigs (both toxoids induce at least 2 units of antitoxin/ml). Pertussis potency is measured by the ability of the vaccine to induce antibodies to pertussis toxoid (PT) and fimbrial hemagglutinin antigen (FHA) in mice. The vaccine is assayed for the presence of active PT using the histamine-sensitizing factor (HSF) test in mice. Thimerosal, aluminum, and free formaldehyde content, sterility, and general safety are determined. The identity of the diphtheria and tetanus components is confirmed by a flocculation test with specific antisera, and the identity of the pertussis component is confirmed by a dot blotting procedure using specific antisera. The vaccine contains unspecified amounts of gelatin (presumably bovine origin) and polysorbate 80 (Tween 80) used during manufacture.
Acellular pertussis concentrate for formulation of Tripedia used in clinical trials was manufactured in either 3,000 or 15,000 liter fermenters and inactivated by 50 days of formalin exposure. Concentrate used in the current/approved vaccine is produced in a 15,000 liter fermenter.
FDA class: Biologic PLA
CBER class: Multiple Antigen Preparations
Approvals: Date = 19920820; PLA/ELA ref. no. 90-0353; Indication = for immunization of children 15 months to 7 years of age (prior to the seventh birthday) who have previously been immunized with three or four doses of whole-cell pertussis DTP (i.e., use as the fourth or fifth dose in the five-dose vaccination regimen having received whole-cells DTP for the first three doses)
Date = 19960700; PLA supplement; Indication = for use in the primary three-dose immunization series for infants, and use as the fourth consecutive dose
Date = 19960927; PLA supplement (no. 95-1267); Indication = for the reconstitution of Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), manufactured by Pasteur Meri-eux Serums et Vaccins, S.A., for immunization of 15-18 month old children [i.e., for mixing with ActHIB to form TriHIBit]
Date = 19991209; approval revoked from Connaught Labs. and reissued to new owner, Aventis Pasteur Inc.
Date = 20000824; PLA supplement; Indication = use of Tripedia for the fifth consecutive dose at 4-6 years of age after 4 prior doses of Tripedia, in the currently recommended childhood immunization series against diphtheria, tetanus, and pertussis; Tripedia can now be used for all five doses (3 primary, 2 booster) of the entire DTP immunization series.
Date = 20010307; PLA supplement; Indication = new formulation without added thimerosal preservative, a 95% reduction in mercury content (some remains from culture media)
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling,]:
Tripedia vaccine is indicated for active immunization against diphtheria, tetanus and pertussis (whooping cough) simultaneously in infants and children 6 weeks to 7 years of age (prior to seventh birthday). Because of the substantial risks of complications of the disease, completion of a primary series of pertussis vaccine early in life is strongly recommended. However, in instances where the pertussis vaccine component is contraindicated, Diphtheria and Tetanus Toxoids Adsorbed (For Pediatric Use) (DT) should be used for each of the remaining doses. (See CONTRAindications: section.)
When Tripedia vaccine is used to reconstitute ActHIB (TriHIBit), the combined vaccines are indicated for the active immunization of children 15 to 18 months of age who have previously been immunized against diphtheria, tetanus and pertussis with three doses consisting of either whole-cell pertussis DTP or acellular pertussis vaccine and three or fewer doses of ActHIB (OmniHIB) within the first year of life for the prevention of invasive diseases caused by H influenzae type b and caused by diphtheria, tetanus, and pertussis. (Refer to ActHIB package insert.)
If passive immunization is required, Tetanus Immune Globulin (Human) (TIG) and/or equine Diphtheria Antitoxin should be used.
Persons who have recovered from culture-confirmed pertussis do not need additional doses of Tripedia vaccine but should receive additional doses of DT to complete the series.
Tripedia vaccine is not to be used for treatment of B. pertussis, C. diphtheriae, or C. tetani infections.
As with any vaccine, vaccination with Tripedia vaccine may not protect 100% of susceptible individuals.
Status: Tripedia received FDA approval in July 1996 for use as the primary three-dose immunization series for infants, and for the fourth consecutive dose. With this approval, Tripedia became the first acellular pertussis vaccine to be licensed for use in infants in the U.S. Tripedia was licensed in Aug. 1996 for the fourth and fifth doses of the five-dose DTP series (3 primary, 2 booster inoculations) for those having already received three doses of a whole-cell DTP vaccine. With its August 2000 approval for use as the fourth or fifth dose in the pediatric series, Tripedia is now approved for all five doses of the pediatric DTP vaccination regimen.
Tripedia was approved in Sept. 1996 for combination with Haemophilus influenzae type b (Hib) conjugate vaccine (ActHIB), forming quadravalent TriHIBit (entry #443).
Tripedia was the first acellular pertussis (DTaP) vaccine recommended over whole-cell DTP for infants by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), and the American Academy of Pediatrics (AAP). An equivalent DTaP combination vaccine was first launched in Japan in 1989.
There are currently no approved non-adjuvant-adsorbed monovalent diphtheria toxoid products (reported by CBER/FDA); and Sanofi Aventis, the largest vaccine company, presumably manufacturers its own diphtheria toxoid vaccine components. The source for the approval of the diphtheria toxoid in this and other combination vaccines from the company containing a diphtheria toxoid component is unclear. The Tripedia approval or approvals for the Sanofi Pasteur’s DT or other DTaP vaccines may effectively cover approval of the diphtheria toxoid component of this and other diphtheria toxoid-containing vaccines from the company.
In March 2004, CBER/FDA reported that Tripedia was one of five vaccines on its “Current list of vaccines using bovine-derived materials from countries on the USDA’s BSE list.” See the Vaccine Products entry (#400) for further information about the use of bovine-derived materials in vaccines and the threat of Bovine Spongiform Encephalopathy (BSE). CBER/FDA also reported “there is no evidence that any case of vCJD [variant Creutzfeld-Jakob disease in humans] has been caused by or is related to vaccines manufactured with bovine-derived materials obtained from countries in which BSE or a significant risk of BSE exists (i.e., countries on the USDA list), and thus the risk of vCJD is theoretical.”
Market: Aventis Pasteur reported $304 million worldwide sales of acellular pertussis vaccines (with/without HIB combination, e.g., TriHIBit) in 1999.
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 $21.40 for ten 1-dose vials. The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $12.65, with this supply contract ending March 31, 2008. 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.
The 2007 Average Wholesale Price (AWP) is $261.80/ten 5-dose vials, with a Direct Price (Manufacturer’s discount price) of $213.94 (Red Book, 2007). This includes the $.75/component vaccine/dose ($2.25/dose of Tripedia) federal excise tax added by the manufacturer to fund the federal vaccine liability insurance program.
The Sanofi Pasteur list price (Jan. 2006) for Tripedia is $191.45 for a purchase of 1-14 packages of ten 1-dose vials ($19.15/dose); and $155.67/package for purchase of 15-44 packages ($15.57/dose); both prices unchanged from Jan. 2003 and 2004.
Companies involvement:
Full monograph
431 DTaP Vaccine/Sanofi USA
Nomenclature:
DTaP Vaccine/Sanofi USA [BIO]
Tripedia [TR]
Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed [FDA]
DTaP Vaccine [SY]
DTPa [CDC abbrev.]
NDC 49281-288-05; NDC 49281-288-15; NDC 49281-557-10; NDC 49281-288-05 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1992
Date of 1st FDA approval = 19920820
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
vaccines, bacterial
vaccines, combination
vaccines, toxoids (inactivated toxins)
bacterial culture <!-- bacterialculture -->
Bordetella pertussis
Clostridium tetani
Corynebacterium diphtheriae
Mueller and Miller medium
peptone (medium)
Stainer-Scholte medium
aluminum potassium sulfate (alum)
ammonium sulfate
Diphtheria Toxoid
filamentous hemagglutinin (FHA), Bordetella pertussis
formaldehyde
gelatin (bovine source)
Pertussis Vaccine Adsorbed, Acellular
phosphate buffer
sucrose
Tetanus Toxoid
thimerosal (mercury derivative)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
bovine source warning, BSE country
North American coral snake
EU000 Not yet/Never filed with EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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