Bordetella pertussis toxoid, recombinant [a component of Pertugen, a DTaP combination vaccine]
Status: BLA filed but withdrawn; formerly used in combination vaccines in Europe
Organizations involved:
Chiron S.p.A. – Manuf.; R&D; Tech.; Europe mark.
Chiron Corp. – Parent
Novartis AG – Parent
Cross ref.: See the entry for DTaP Vaccine/Chiron (Pertugen; Triacelluvax) combination vaccine, of which this is a component (of the vaccine’s pertussis vaccine component). See the Acellular Pertussis Vaccine Products entry, the Diphtheria and Pertussis Toxoids entry, and the Pertussis Vaccine (DTP/DTaP) Products entry.
Description: This recombinant Bordetella pertussis toxoid (inactivated form of B. pertussis toxin) mutein (altered sequence) expressed by plasmid-transformed Escherichia coli (E. coli) bacteria was a component of the pertussis vaccine component [along with conventional Bordetella pertussis fermentation-derived filamentous hemagglutinin (FHA) and pertactin (69 kDa protein)] of a triple combination DTaP vaccine (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed), formerly marketed as Pertugen and Triacelluvax.
Pertussis toxin has been inactivated/detoxified by genetic manipulation. The S1 subunit of the pertussis toxin gene/protein has been modified, apparently at position 129, with glutamic acid substituted by glycine, and at position 9, with arginine substituted by glycine, as indicated by U.S. patent 5,889,172.
Nomenclature: Pertussis Toxoid, rDNA [BIO]; Bordetella pertussis toxin, rDNA [SY]; pertussis toxoid, recombinant [SY]; PT, rDNA [SY]
Biological.: The change of B. pertussis from phase I (virulent/pathogen) to phase III (non-virulent) is particularly associated with loss of ability to express pertussis toxin (PT) and adenylcyclase (Adc). Pertussis toxin, a protein with a molecular weight of about 100,000 Dalton (100 kDa), is produced and released into the extra cellular environment by Bordetella pertussis during phase I. PT has enzymatic activity and deactivates ADP-ribosilandol, a GTP-dependent protein which is involved in the deactivation of cellular adenylcylase, leading to toxic effects.
Like other bacterial toxins, pertussis toxin is composed of two different fragments/subunits, A and B, with different functionality – A comprising the S1 subunit, and B comprising S2, S3, S4 and S5 subunits – in two dimers D1 (S2+S4) and D2 (S3+S4) linked to each other by the S5 subunit. The A fragment, which is toxic, comprises a single polypeptide S1 (subunit S1) having a molecular weight of about 28,000 Daltons (28 kDa), which can bind an ADP-ribose group to a GTP-binding protein G, and inhibits adenylate cyclase involved in the transmission of signals from the outside to the inside of cells. The B fragment comprises five polypeptides S2, S3, S4 and S5 (subunits S2, S3, S4, S5) with molecular weights of 23,000 (23 kDa), 22,000 (22 kDa), 12,000 (12 kDa) and 9,000 Daltons (9 kDa), respectively, disposed as two dimers S2+S4 and S3+S4 and a monomer S5. The B fragment binds to receptors of eucaryotic cells facilitating entry of S1, the active toxin, into the cells.
Conventional physical methods for pertussis toxin inactivation methods, e.g., heat treatment, may not completely inactivate the toxin, and chemical inactivation may lead to variable results, potentially causing side effects which vary from simple flushing to permanent neurological damage and/or death. Recombinant DNA methods allow expression of acellular pertussis toxoid (inactivated toxin) without the need to inactivate the toxin.
Companies.: This component was developed by Biocine S.p.A. (Chiron S.p.A), a subsidiary of Chiron Corp., which merged into Novartis AG in Oct. 2005.
Status: Pertugen was formerly approved in Europe and marketed in Italy by Chiron S.p.A.. a subsidiary of Chiron Corp., which merged into Novartis AG in Oct. 2005. Chiron filed for U.S. approval, but the PLA was withdrawn prior to approval. See the entry for Pertugen/Triacelluvax for further information.
Tech. transfer: U.S. patents covering aspects of this recombinant pertussis vaccine include 6,350,612; 5,889,172; 5,785,971; and 5,427,788, assigned to Chiron S.p.A. These patents describe cloning and sequencing of the Eco RI fragment of B. pertussis chromosomal DNA with 4,696 base pairs, containing the genes for five subunits of pertussis toxin, and inactivated recombinant toxins (toxoids).
Index Terms:
Companies involvement:
Full monograph
236 Pertussis Toxoid, rDNA
Nomenclature:
pertussis toxoid, rDNA [BIO]
Bordetella pertussis toxoid, recombinant [SY]
PT, rDNA [SY]
FDA Class: Biologic PLA
biopharmaceutical products
enzymes
exempt from CBER lot release requirements
recombinant DNA
vaccines, bacterial
vaccines, subunit
vaccines, subunit
bacterial culture <!-- bacterialculture -->
Bordetella pertussis
Escherichia coli (E. coli)
pertussis toxin (PT)
apheresis (hemapheresis)
FD&C Yellow 5
North American coral snake
North American coral snake
EU003 EU application withdrawn
UM999 Not Available/Not Marketed in US
US01 FDA application withdrawn or rejected
EM999 Not Available/Not Marketed in EU
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