Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed - Certiva; Certiva-EU; DTaP
Status: FDA and EU approvals revoked
Organizations involved:
North American Vaccine, Inc. – Manuf.; R&D; Tech.; USA mark.; Former
Baxter Hyland Immuno – Parent; Former
Abbott Laboratories – USA mark.; Former
National Institute of Child Health and Human Development (NICHD), NIH – R&D; Tech.
National Institutes of Health (NIH) – Parent org.
Statens Seruminstitut – Manuf. other; Europe mark.; Former
Chiron Behring GmbH – Europe mark.; Former
Cross ref: See the entries for Pertussis Vaccines, Acellular (#506) and the Diphtheria and Tetanus Toxoids and Pertussis Vaccine (DTP/DTaP) Products (#429). See also the entries for two components of this combination vaccine – Tetanus Toxoid Concentrate (For Further Manufacturing Use) (#546), and Diphtheria Toxoid Concentrate (For Further Manufacturing Use) (#420). See the entries for Tetanus Toxoid Products (#543); and Diphtheria Toxoid Products (#418).
Note, although the acellular pertussis toxoid component of this vaccine is unique and Certiva represented its first approval for the U.S. market, this component has not received separate approval. This entry includes description of this novel pertussis toxoid.
Description: Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed or Certiva is a combination (DTaP) vaccine, composed of conventional Diphtheria Toxoid and Tetanus Toxoid (inactivated toxins), and a novel acellular pertussis toxoid component consisting of a single purified pertussis toxin detoxified (converted to a toxoid) by oxidation with hydrogen peroxide (H2O2), with each toxoid independently adsorbed onto aluminum hydroxide adjuvant.
The vaccine is no longer manufactured. A slightly different formulation, Certiva-EU, was marketed in Europe.
Each 0.5 mL dose of vaccine is formulated to contain 15 Lf diphtheria toxoid, 6 Lf tetanus toxoid, 40 µg pertussis toxoid, 0.5 mg aluminum as aluminum hydroxide, and is preserved with 0.01% thimerosal (mercury derivative). The residual free formaldehyde content by assay is less than or equal to 10 ppm. The diphtheria and tetanus toxoids each induce not less than 2 units of antitoxin per mL in the guinea pig potency test. The potency of the pertussis toxoid is evaluated by measurement of antibody titers to pertussis toxin in immunized mice using an ELISA. The product may contain residual fetuin, a bovine protein used for affinity purification of the pertussis component. The pertussis toxoid component contains less than 80 nanograms of fetuin in 40 µg of pertussis toxoid. The dating period (at time of approval) for Certiva is 18 months stored at 2-8˚C (refrigerated). The provisional dating period for each bulk component is 5 months from the date of adsorption onto aluminum hydroxide.
Nomenclature: DTaP Vaccine/NAVA [BIO]; Certiva [TR USA]; Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed [FDA]; NICHD-Ptxd [SY or pertussis toxoid component]; Certiva-EU [TR for European formulation]; DTPa [CDC]; NDC 62448-4012-1 [NDC]
Companies.: The product, particularly the hydrogen peroxide-inactivated pertussis toxoid, was developed and manufactured by North American Vaccine, Inc. (NAVA; Belts-ville, MD), CBER/FDA est. no. 1254. NAVA was acquired in June 2000 by Baxter International, Inc. and is now a merged into Baxter Hyland Immuno. The diphtheria toxoid and tetanus toxoid components were obtained from Statens Seruminstitut. See the related entries (#420, #547) regarding these two intermediates.
Both Abbott Labs. and NAVA marketed Certiva in the U.S. Abbott originally held exclusive marketing rights for the U.S. private sector (physicians), while NAVA held rights for institutional/government sales. Chiron Behring and the Statens Seruminstitut held certain European marketing rights and marketed it in Europe. In late 1999, Abbott terminated its marketing agreement with NAVA, withdrawing from U.S. marketing of the vaccine.
Manufacture of Certiva was suspended by NAVA in late 1999 in favor of manufacturing NeisVac-C meningococcal vaccine for the U.K. market. NAVA continued to sell its stocks of Certiva to U.S. governmental organizations and provided it to its European marketing partners. NAVA, now merged into Baxter, never resumed manufacture of Certiva.
Bulk diphtheria and tetanus toxoids for further manufacturing by NAVA are manufactured by Statens Seruminstitut (Copenhagen, Denmark).
Manufacture: Pertussis toxin (PT) was isolated from Phase 1 Bordetella pertussis cultured in a modified Stainer-Scholte medium. PT was purified by affinity chromatography, including the use of fetuin (a bovine serum protein) as an affinity ligand. PT was detoxified (oxidized) using hydrogen peroxide according to methods licensed from the National Institute of Child Health and Development (NICHD), National Institutes of Health (see the Tech. transfer section). Each component vaccine was adsorbed onto aluminum hydroxide adjuvant, mixed/formulated, and the vaccine packaged in vials.
NAVA experienced problems manufacturing large volumes of Certiva in 1999, with manufacturing limited by their in-house supply of sterile water for injection and difficulties in scaling-up large-scale fermentation. In June 1999, the company announced it had enhanced its water system and planned to fortify the pertussis growth media, allowing for a 300% increase in production capacity. However, manufacture of Certiva and Certiva-EU was halted in late 1999.
FDA class: Biologic BLA
CBER class: Multiple Antigen Preparations
Approvals: Date = 19980729; first approval; BLA
Status: Approval was recently voluntarily revoked by Baxter (between Jan.-April 2004). A different formulation (Certiva-EU) was approved and is marketed in the European Union.
In Dec. 2000, CBER/FDA reported that the Tetanus Toxoid component of Certiva was manufactured by Statens Seruminstitut using bovine-derived materials from countries on the USDA list of countries known to have cattle with BSE. See the Regulatory section of the Vaccine Products entry (#400) for further information about BSE concerns. Presumably, by now (and particularly for the product marketed in Europe), these concerns about sourcing of materials used in manufacture have been resolved.
Tech. transfer: NAVA exclusively licensed acellular pertussis toxoid technology from the National Institutes of Health (NIH; Bethesda, MD) including U.S. 4,762,710. The acellular pertussis toxoid component consisting of a monocomponent purified pertussis toxin is detoxified (converted to a toxoid) by oxidation with hydrogen peroxide (H2O2). This process was invented by investigators with the National Institute of Child Health and Development (NICHD), NIH.
Trials: Approval of Certiva was supported by a number of U.S. and foreign clinical studies, including a double-blind, randomized, placebo-controlled efficacy trial conducted in Goteborg, Sweden involving 3,450 Swedish infants sponsored by the National Institute of Child Health and Human Development (NICHD, NIH). U.S. safety studies involving 3,715 infants and children were sponsored by NAVA, NICHD and National Institute of Allergy and Infectious Diseases (NIAID; NIH). The efficacy observed with Certiva-EU in Sweden was especially significant since the clinical study was conducted during an epidemic of pertussis. In U.S. clinical trials, Certiva had fewer local and systemic adverse effects compared to a whole cell DTP vaccine.
Tech. transfer: Allowing for the time spent in clinical trials and during FDA regulatory review (under 35 USC §156), the expiration date for U.S. patent 4,762,710, assigned to NIH was extended (4.95 years; near the 5-year max.) to May 28, 2011.
Medical: Pertussis toxin antibody levels induced by 50 µg of the hydrogen peroxide-inactivated toxin have been shown to equal those in adults recovering from pertussis. In Feb. 1999, North American Vaccine reported, “The vaccine has been used universally in Denmark since 1997 and no serious vaccine associated adverse events have been reported after administration of more than 300,000 doses of the vaccine since the product was first launched. This is consistent with the data from the safety and efficacy studies submitted to support approval. In those studies, none of the infants and children who received the DTaP-IPV or DTaP vaccine experienced hypotonic hypo-responsiveness (collapse) episodes and the rates of local reactions, such as soreness, redness and swelling, were very low. Moreover, surveillance and epidemiologic studies in Goteborg, Sweden for more than a decade, along with the results from efficacy trials and a Swedish effectiveness study, establish that the Company’s pertussis toxoid protects vaccine recipients and established herd immunity.”
Market: While still available, the National Immunization Program, Centers for Disease Control and Prevention (CDC), had reported the private sector list price for Certiva was $17.06/dose. The cost included $.75/component vaccine/dose ($2.25/dose for Certiva) federal excise tax funding federal vaccine liability insurance. CDC reported that it purchased the vaccine in bulk for $9.25/dose (contract ending 3/31/01).
Companies involvement:
Full monograph
434 DTaP Vaccine/NAVA
Nomenclature:
DTaP Vaccine/NAVA [BIO]
Certiva [TR]
Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed [FDA]
DTaP vaccine [SY]
NICHD-Ptxd [pertussis vaccine component] [SY]
Certiva-EU [TR for European formulation]
DTPa [CDC abbrev.]
NDC 62448-4012-1 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 1998
Date of 1st FDA approval = 19980729
(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
aluminum hydroxide
Diphtheria Toxoid
fetuin
formaldehyde
Pertussis Vaccine Adsorbed, Acellular
Sterile Water for Injection
Tetanus Toxoid
thimerosal (mercury derivative)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
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
North American coral snake
Park-William no. 8, Corynebacterium diphtheriae
EU011 Approved Formerly in EU/withdrawn
UM999 Not Available/Not Marketed in US
US011 Approved Formerly in US/withdrawn
EM999 Not Available/Not Marketed in EU
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