Status: approved; marketed

Organizations involved:

Sanofi Pasteur Inc. – USA mark.

Sanofi Pasteur Ltd. – Manuf.; R&D; Tech.

Sanofi Pasteur S.A. – Parent

Cross ref.: See the entries for Acellular Pertussis Vaccine Products (#506); Diphtheria and Pertussis Toxoids and Pertussis Vaccine (DTP/DTaP) Products (#429); and the other DTaP vaccine, Tripedia (#431), from Sanofi Pasteur. See the entries for Tetanus Toxoid Products (#543); and Diphtheria Toxoid Products (#418). See also entries for the diphtheria and tetanus toxoid components of this vaccine from Sanofi Pasteur.

Description: Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) or Daptacel is a trivalent combination DTaP vaccine including three component vaccines – diphtheria toxoid, tetanus toxoid, and acellular Bor-detel-la pertussis vaccine – each adsorbed on aluminum phosphate adjuvant, in a sterile isotonic sodium chloride solution. Daptacel is a thimerosal (mercury-based preservative)-free formulation. Each dose of Daptacel contains as active ingredients five acellular B. pertussis antigens [pertussis toxoid (PT), 10 µg ; filamentous hemagglutinin (FHA), 5 µg; pertactin (PRN) 3 µg and; fimbriae agglutinogen (Agg) types 2 and 3, 5 µg]; diphtheria toxoid, 15 Lf and; tetanus toxoid, 5 Lf. Other ingredients per dose include 3.3 mg (0.6% v/v), 2-phenoxy-ethanol as antimicrobial preservative, 0.33 mg of aluminum (adjuvant; see #939), ≤0.1 mg residual formaldehyde, and <50 ng residual glutaraldehyde.

Both diphtheria and tetanus toxoids induce at least 2 units of antibodies (antitoxin) per mL in the guinea pig potency test. The potency of the acellular pertussis vaccine components is evaluated by the antibody response of immunized mice to pertussis toxin, FHA, PRN, and fimbriae types 2 and 3 as measured by enzyme-linked immunosorbent assay (ELISA).

Daptacel is packaged in 0.5 mL single dose vials sold singly and in packages of five. Daptacel should be stored at 2-8°C (refrigerated). The dating period for the final fill of the combination product when stored continuously at 2-8˚C is 30 months from the date of manufacture, defined as the date of the initiation of the earliest valid potency test of the final bulk, regardless of which component of the final bulk is tested first.

Nomenclature: DTaP Vaccine/Sanofi Canada [BIO]; Dapta-cel [TR]; Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) [FDA]; DTaP vaccine [SY]; DTPa [CDC]; CP10/5/5/3 [SY]; NDC 49281-286-01 and NDC 49281-286-05 [NDC]

Companies.: Daptacel was developed and components and final vaccine are manufactured and packaged by Sanofi Pasteur Ltd., CBER/FDA est. no. 1726. It is marketed in the U.S. by Sanofi Pasteur Inc.

Manufacture: The acellular pertussis vaccine components are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium modified by the addition of casamino acids and dimethyl beta-cyclodextrin. The fimbriae types 2 and 3 are extracted from the bacterial cells. The pertussis toxin, filamentous hemagglutinin (FHA) and pertactin (PRN) are prepared from the culture supernatant. These proteins are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. Pertussis toxin is inactivated with glutaraldehyde and FHA is treated with formaldehyde. The individual pertussis antigens are adsorbed separately onto aluminum phosphate. See also the “Tech. Transfer” section for information about manufacture of the fimbrial pertussis components.

Diphtheria toxoid is obtained from Corynebacterium diphtheriae grown in modified Mueller’s growth medium. After ammonium sulfate fractionation, the diphtheria toxin is detoxified (converted to toxoid) with formalin, diafiltered, and adsorbed onto aluminum phosphate.

Tetanus toxoid is obtained from Clostridium tetani grown in modified Mueller-Miller casamino acid medium (without beef heart infusion). Tetanus toxin is detoxified with formalin, purified by ammonium sulfate fractionation and diafil-tra-tion, and adsorbed onto aluminum phosphate.

The component vaccines individually adsorbed onto aluminum phosphate are combined in a sterile isotonic sodium chloride solution containing 2-phenoxyethanol as preservative.

FDA class: Biologic BLA

CBER class: Multiple Antigen Preparations

Approvals: Date = 20020514; BLA; Indication = active immunization of infants and toddlers at 2, 4, 6, and 17-20 months of age four consecutive doses (administered at 2, 4, 6, and 15 to 20 months of age)

Date = 20061006; BLA supplement (BL 103666/5071); Indication = revised insert/labeling

Date = 20080312; BLA supplement; Indication = approved as as a fifth consecutive diphtheria, tetanus, and acellular pertussis (DTaP) vaccine dose for children 4 years through 6 years of age for the prevention of diphtheria, tetanus, and pertussis (now licensed for the entire immunization series)

Indications: [portion of the "INDICATIONS AND USAGE” section of product insert/labeling; 12/26/2008]:

DAPTACEL is indicated for active immunization against diphtheria, tetanus and pertussis in infants as a five dose series in infants and children 6 weeks through 6 years of age (prior to seventh birthday).

Status: Daptacel was originally approved for only the first four consecutive doses of the recommended childhood immunization series against diphtheria, tetanus, and pertussis (at ages 2, 4, 6, and 17-20 months). Sanofi Pasteur received approval for use as the fifth dose in March 2008. The approval of the fifth consecutive dose of Daptacel vaccine completes the FDA license for the entire five-dose DTaP vaccine series enabling health-care professionals to administer the same brand of DTaP vaccine for the series as recommended by the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP).

Tech. transfer: U.S. patent 6,399,076, “Acellular pertussis vaccines and methods of preparation thereof,” assigned to Aventis Pasteur Ltd. (Sanofi Pasteur Ltd.), June 4, 2002, covers aspects of Daptacel, particularly its unique fimbrial agglutinogens. Fimbrial agglutinogens are prepared from B. pertussis by a multiple step procedure involving extraction of the fimbrial agglutinogens from cell paste, and concentration and purification of the extracted material. As described in Example 1, agglutinogens are extracted from B. pertussis cell paste using a urea-containing buffer, e.g., 10 mM potassium phosphate, 150 mM NaCl and 4M urea. Clarified supernatant is concentrated and diafiltered, e.g., against 10 mM potassium phosphate/150 mM NaCl/0.1% Triton X-100 (octoxynol) using a 100-300 kDa NMWL membrane filter. This is concentrated, e.g., by addition of polyethylene glycol of m.w. about 8000 (PEG 8000). A third precipitate is extracted, e.g., with a buffer comprising 10 mM potassium phosphate/150 mM NaCl to provide crude fimbrial agglutinogen-containing solution, which is purified by column chromatography, e.g., using a silica column, to produce the fim-brial agglutinogen preparation in the run-through. This is further concentrated and diafiltered to provide the final purified fimbrial agglutinogen preparation containing fimbrial agglutinogen 2 and 3.

Trials: Daptacel demonstrated a high level of protection against pertussis disease in a randomized, double-blind, placebo controlled trial sponsored by the National Institute of Health (NIH). See the New England Journal of Medicine (1996;334:349-355).

Following administration of Daptacel vaccine as the fifth dose, more than 93% of subjects experienced a booster response to each of the pertussis components. Additionally, all participants (100%) achieved antibody responses greater than or equal to 0.1 IU/mL for both the tetanus and diphtheria antigens, indicating that protective levels had been achieved. In assessing long-term protection, the study found that 99.6% (250/251) and 98.8% (248/251) of subjects achieved levels greater than or equal to 1.0 IU/mL for diphtheria and tetanus, respectively.

Medical: Daptacel vaccine is given to infants and children 6 weeks through 6 years (prior to 7th birthday) to prevent 3 serious diseases: diphtheria, tetanus (lockjaw), and pertussis (whooping cough).

Market: Daptacel is the fifth and most recent acellular pertussis component-containing vaccine to have received FDA approval. Of these, only two others, Tripedia also from Sanofi Aventis and Infanrix from GlaxoSmithKline, are also currently distributed 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 $22.04 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 $13,25, with this supply contract ending March 31, 2008. These prices include the $2.25/dose ($.75/covered component vaccine) Federal Excise Tax.

The 2007 Average Wholesale Price (AWP) is $259.98 for 10 vials, with a Direct Cost (DC; manufacturer’s discount) of $220.40 (no change from 2004) (Red Book, 2007; no change since at least 2005). This includes $.75/component vaccine/dose ($2.25/dose of Daptacel) federal excise tax (to fund the federal vaccine liability insurance program) charged by the manufacturer.

The Jan. 2006 Aventis Pasteur list price for Daptacel is $197.90 for purchase of 1-15 packages of ten 1-dose vials ($19.79/dose; same in Jan. 2004); and $155.67/package for purchase of 14-44 packages of ten vials ($15.57/dose; same in Jan. 2004).