title: Roads from vaccines to therapies.
abstract: Over the past decade, we have demonstrated that various recombinant fragments of botulinum neurotoxin are highly immunogenic, stimulating notable levels of protective antibodies in mice, guinea pigs, and nonhuman primates. One of the fragments evaluated, the fragment C, is a potential next-generation vaccine candidate to replace the current pentavalent botulinum toxoid vaccine. Synthetic genes encoding the carboxyl-terminal regions (approximately 50 kDa) of toxin types A, B, C1, E, and F were expressed in Pichia pastoris, and manufacturing processes were developed for producing highly purified vaccines. These vaccines were shown to be safe, highly efficacious, stable, and amenable to high-level industrial production. Recombinant vaccines are now being produced in accordance with current Good Manufacturing Practices for use in future clinical trials. As our discovery-based program on vaccine development is diminishing, it is concurrently being replaced with a program focused on developing therapeutic interventions to botulism. Synthetic genes encoding the light chains of botulinum toxin have been expressed in Escherichia coli, and purified. These proteolytically active light chains are being used in high-throughput assays to screen for inhibitors of its catalytic activity. Other resources developed as part of the vaccine initiative, likewise, are finding utility in the quest to develop therapies for botulism.
authors.affiliation: Division of Toxinology and Aerobiology, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702-5011, USA. leonard.smith@amedd.army.mil
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Smith
authors.forename: Melody J
authors.initials: MJ
authors.lastname: Jensen
authors.forename: Vicki A
authors.initials: VA
authors.lastname: Montgomery
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Brown
authors.forename: S Ashrat
authors.initials: SA
authors.lastname: Ahmed
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001906:Botulism / Q000276:immunology / Q000517:prevention & control*; D004306:Dose-Response Relationship, Immunologic; D004926:Escherichia coli / Q000276:immunology; D029968:Escherichia coli Proteins / Q000276:immunology; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology; D018052:Pichinde virus / Q000276:immunology; D014612:Vaccines / Q000627:therapeutic use*; D014614:Vaccines, Synthetic
chemical_list: D029968:Escherichia coli Proteins; D010446:Peptide Fragments; D014612:Vaccines; D014614:Vaccines, Synthetic; D001905:Botulinum Toxins