Tetanus Toxoid, Reduced Diphtheria Toxoid and Acell-u-lar Pertussis Vaccine Adsorbed - Boostrix; dTpa; Tdap
Status: marketed in U.S.
Organizations involved:
GlaxoSmithKline Biologicals S.A. – Manuf.; R&D; Tech.
GlaxoSmithKline Inc. – USA mark.
GlaxoSmithKline plc – Parent
Chiron Behring GmbH & Co. KG – Manuf. other
Chiron Corp. – Parent
Novartis AG – Parent
Cross ref: See the entries for Pertussis Vaccines, Acellular (#506); Diphtheria and Pertussis Toxoids and Pertussis Vaccine (DTP/DTaP) Products (#429); Tetanus Toxoid Vaccines (#543); and Diphtheria Toxoid Products (#418). See the entry for Diphtheria & Tetanus Toxoids, conc. (#422), an intermediate/precursor used for manufacture of Boostrix.
Description: Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed or Boostrix is a diptheria, tetanus and acellular pertussis (dTpa, DTaP-type) vaccine with reduced (booster) doses of each antigen to be used as a booster vaccine in adults and children 10 to 18 years old previously vaccinated against these diseases. The vaccine contains tetanus toxoid, diphtheria toxoid, and pertussis antigens (inactivated pertussis toxin [PT] and formaldehyde-treated filamentous hemagglutinin [FHA] and pertactin [69 kDa outer membrane protein]) adsorbed onto aluminum hydroxide. The antigens are the same as those in Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed), but Boostrix is formulated with reduced quantities of these antigens. Relative to Infanrix, Boostrix contains approximately one-tenth diphtheria toxoid, one-half tetanus toxoid, and one-third each of the pertussis antigens (PT, FHA and pertactin).
Each 0.5 mL dose contains 2.5 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid, 2.5 µg of pertactin, 8 µg of FHA, and 8 µg of inactivated PT. Tetanus and diphtheria toxoid potency is determined by measuring the amount of neutralizing antitoxin in previously immunized guinea pigs. The potency of the acellular pertussis components is determined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice. Each 0.5-mL dose also contains 4.5 mg of sodium chloride, aluminum adjuvant (not more than 0.39 mg aluminum by assay), ≤100 µg of residual formaldehyde, and ≤100 µg of polysorbate 80 (Tween 80). This vaccine contains no preservative. The dating period for Boostrix is 36 months from the date of manufacture of the final bulk when stored at 2-8°C (refrigerated). The date of manufacture is the date of initiation of the last valid potency test for the component tested first.
A similar formulation has been available in Australia and a number of countries in Europe, South America and Asia. The U.S. formulation contains the same amounts of each antigen, but U.S. Boostrix contains less aluminum adjuvant and is preservative free. The non-U.S. Boostrix has more aluminum adjuvant and contains 2-phenoxyethanol as a preservative. Each of the components (as appoved in Australia) is adsorbed on aluminium hydroxide or aluminium phosphate, and suspended in isotonic sodium chloride, with each dose containing 0.5 mg aluminum.
Nomenclature: dTpa booster/GSK [BIO]; Boostrix [TR]; Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed [FDA]; Tdap [SY]; dTpa [SY]
Companies.: Boostrix was developed, the acellular pertussis components are manufactured, and finishing (blending, filling, testing, packaging) performed by GlaxoSmithKline Biologicals S.A., CBER/FDA est. no. 1617. The vaccine is marketed in the U.S. by GlaxoSmithKline Inc.
Diphtheria and tetanus toxoid components used in manufacture of the vaccine [Diphtheria and Tetanus Toxoids Adsorbed Combined Bulk (For Further Manufacturing Use), and Tetanus Toxoid Concentrate (For Further Manufacturing Use)] are manufactured by Chiron Behring GmbH & Co. KG (Marburg, Germany), Chiron Corp., which merged into Novartis AG in Oct. 2005.
Manufacture: Tetanus toxin is produced by culturing Clostridium tetani in a modified Latham medium derived from bovine casein, detoxification of the toxin with formaldehyde, concentration by ultrafiltration, purification by precipitation, dialysis, and sterile filtration. The diphtheria toxin is similarly produced by growing Corynebacterium diphtheriae in Fenton medium containing a bovine extract, detoxification of the toxin with formaldehyde, concentration by ultrafiltration, purification by precipitation, dialysis, and sterile filtration.. The bovine materials used in these extracts are sourced from countries which the U.S. Dept. of Agriculture (USDA) has determined neither have nor are at risk of bovine spongiform encephalopathy (BSE). The three acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella pertussis culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated from the fermentation broth; pertactin is extracted from the cells by heat treatment and flocculation. The antigens are purified in successive chromatographic and precipitation steps. PT is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with formaldehyde. Each antigen is individually adsorbed onto aluminum hydroxide. All antigens are then diluted and combined to produce the final formulated vaccine.
FDA class: Biologic BLA
Approvals: Date = 20050503; BLA; Indication = booster immunization against tetanus, diphtheria and pertussis as a single dose in adolescents 10-18 years of age
Date = 20051229; BLA supplement; Indication = addition of clinical safety information to the package insert
Date = 20081204; BLA supplement; Indication = approval for use in adults 10-64 years old
Indications: [full text of the "Indications AND USES” section of product insert/labeling; 5/2009]:
BOOSTRIX is a vaccine indicated for active booster immunization against tetanus, diphtheria, and pertussis as a single dose. BOOSTRIX is approved for use in individuals 10 through 64 years of age.
Status: On July 7, 2004, GSK filed a BLA for Boostrix. On March 15, 2005, the Vaccines and Related Biological Products Advisory Committee, FDA, voted unanimously to recommend licensure of Boostix for its approved indications:. Approval was granted on May 3, 2005 (approval time = <10 months).
As part of its approval, FDA specified that GSK conduct post-marketing clinical studies, including a randomized, partially blinded, comparative study evaluating safety and immunogenicity when Boostrix vaccine is given concomitantly with Menactra in ~1,335 adolescents aged 11-18 years, with the final study protocol to be submitted by Oct. 31, 2005, the study initiated by Feb. 28, 2006; and the final study report to be submitted by Sept. 30, 2008. GSK must also submit data from a study in which subjects receive Boostrix following five doses of Infanrix in childhood, with this to be submitted by June 30, 2005; and conduct an open label, safety surveillance study in >10,000 subjects, with the study protocol submitted by Nov. 30, 2005, the study initiated by Feb. 28, 2006, completed by June 30, 2007, and the final report will be submitted by June 30, 2008.
On May 3, 2005, FDA approved a BLA from Chiron Vaccines, now merged into Novartis AG, for the tetanus toxoid adsorbed component of Boostrix.
In Jan. 2008, GSK launched Boostrix in India.
In Jan 2008, GSK reported the vaccine was " well accepted [presumably, marketed] in 58 countries."
In Dec. 2008, Boostrix received supplemental approval for use in adults 10-64 years old (then the broadest age range for any Tdap vaccine). This approval effectively extended the whooping cough protection afforded by Boostrix in adolescents to adults 19-64, expanding options for adult Tdap vaccination.
Trials: Boostrix has been shown to be safe and effective in its clinical trials. An observer-blinded, randomized, controlled, multi-center Phase III trial of safety and immunogenicity was conducted in 4,114 healthy adolescents aged 10-18 years. Each subject had completed his or her routine childhood vaccinations against diphtheria, tetanus and pertussis according to the recommended schedule. In both treatment groups, ≥99.9% of the subjects had diphtheria and tetanus antibody titers each ≥0.1 IU/mL, indicating seroprotection. Pertussis antibody levels, including for each pertussis component (pertussis toxin, fimbrial hemagglutinin antigen, and pertactin) exceeded by 1.8-6.9 times those observed in infants following immunization with Infanrix, GSK’s conventional, primary-vaccination DTaP vaccine. GSK reports that the vaccine’s safety is “comparable” to an approved combined diphtheria and tetanus (DT) vaccine, used as placebo in trials. However, there was more mild to moderate pain reported in patients who got Boostrix, but rates of severe pain were equal between Boostrix and DT vaccine. Some may interpret this to mean that Adacel (a comparable dTpa vaccine from Sanofi Pasteur) is safer or more preferable than Boostrix.
In Oct. 2005, results were reported from a double-blind, placebo (Havrix)-controlled U.S. trial in 2,781 at-risk adolescent and adults subjects. Boostrix was 92% effective in providing protection from disease, with one case among Boostrix recipients and 9 cases among placebo recipients.
The Dec. 2008 approval of Boostrix in adults was based on two trials in which nearly 3,000 U.S. subjects 19-64 years of age were vaccinated with Boostrix. The data demonstrated the overall safety and immunogenicity of Boostrix in providing booster protection against tetanus, diphtheria and whooping cough in adults..
Medical: A single 0.5 mL dose is administered intramuscularly. Boostrix can be given if at least five years have elapsed since the last recommended series of childhood diphtheria, tetanus and pertussis vaccinations.
dTpa vaccines, Adacel and Boostrix, are used in adolescents to reduce the increasing incidence of pertussis as immunity from a course of infant vaccination wanes. Many children already receive a booster at about age 11 or 12 against tetanus and diphtheria, and new dTpa vaccines simply add a pertussis, or whooping cough, component.
Market:
First-half 2013 sales were $165 million. 2012 sales are estimated at about $300 million.
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 $36.25 for packages of 10 single-dose vials and 5 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 $30.75 for packages of 10 single-dose vials and 5 prefilled syringes. These prices include the $2.25/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. GSK’s contract with NIP, CDC, expires on March 31, 2007.
The 2007 Average Wholesale Price (AWP) is $215.25/five single-dose vials, $430.50 for 10 (Red Book, 2007). This included the $2.25/dose ($.75/covered component vaccine) Federal Excise Tax.
Another DTaP-type booster vaccine, Adacel (see related entry), directly competes against Boostrix. Adacel is approved for a much broader age range than Boostrix.
Ongoing: GSK is conducting clinical trials with Boostrix as a booster vaccine in adults.
Companies involvement:
Full monograph
436 dTpa booster/GSK
Nomenclature:
dTpa booster/GSK [BIO]
Boostrix [TR]
Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed [FDA]
dTpa [SY]
Tdap [SY used by GSK in U.S.]
FDA Class: Biologic BLA
Year of approval (FDA) = 2005
Date of 1st FDA approval = 20050503
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
vaccines, bacterial
vaccines, combination
vaccines, toxoids (inactivated toxins)
bacterial culture <!-- bacterialculture -->
Bordetella pertussis
casamino acids
Clostridium tetani
Corynebacterium diphtheriae
Feiba bulk powder
Stainer-Scholte medium
aluminum hydroxide
dipalmitoylphosphatidylcholine (DPPC)
Diphtheria Toxoid
filamentous hemagglutinin (FHA), Bordetella pertussis
formaldehyde
glutamine synthetase (GS) expression system
pertactin (69 kDa protein)
pertussis prophylaxis
Pertussis Vaccine Adsorbed, Acellular
sodium chloride
Tetanus Toxoid
Tetanus Toxoid Adsorbed
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
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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