Developing Test Methods to Measure the Potency of Vaccine(s) and Antitoxin(s) against Botulism and Tetanus

Principal Investigator: James E. Keller, PhD
Office / Division / Lab: OVRR / DBPAP / LRSP

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Overview

Public Health Issue: Clostridial neurotoxins are produced by different strains of either Clostridium botulinum or Clostridium tetani. Each type of neurotoxin will cause botulism or tetanus, which are potentially fatal neuromuscular diseases characterized by progressive muscle weakness (botulism) or progressive muscle contraction (tetanus). Both neurotoxins act within nerve terminals where they prevent the nerve from communicating with neighboring cells. Because of this and other properties, botulinum neurotoxin is classified by the CDC as a Category A biological weapon.

Regulatory Contribution: Vaccines and antitoxin products directed against tetanus or botulinum neurotoxins cannot be ethically tested in human subjects because the disease challenge can be lethal. Therefore, this research program helps develop and evaluate nonclinical methods to evaluate the quality of vaccines and antitoxins that are intended to block the action of either toxin.

Research Approach: We develop new tests for assessing the quality and effectiveness of anti-botulinum and anti-tetanus products. Examples include the development of non-lethal alternative animal models, neuronal cell culture and cell-free biology assays that are used to evaluate the toxin, antigens or antibodies. The results provide a greater understanding of the molecular mechanisms for each neurotoxin as well as developing practical methods to evaluate vaccines to each.

Mission Relevance & Outcomes: These studies will provide tools for evaluating and supporting the development of effective potency assays to test vaccine, antitoxin or other drug regimens intended to hasten recovery or prevent disease.

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Publications

Clin Vaccine Immunol 2008 Sep;15(9):1374-9
Characterization of new formalin-detoxified botulinum neurotoxin toxoids.
Keller JE

Infect Immun 2006 Oct;74(10):5617-24
Comparison of extracellular and intracellular potency of botulinum neurotoxins.
Cai F, Adrion CB, Keller JE

Neuroscience 2006;139(2):629-37
Recovery from botulinum neurotoxin poisoning in vivo.
Keller JE

Biochemistry 2004 Mar 2;43(8):2209-16
Role of metals in the biological activity of Clostridium botulinum neurotoxins.
Eswaramoorthy S, Kumaran D, Keller J, Swaminathan S

Biochemistry 2004 Jan 20;43(2):526-532
Uptake of Botulinum Neurotoxin into Cultured Neurons.
Keller JE, Cai F, Neale EA