Citation

Vitetta ES, Smallshaw JE, Coleman E, Jafri H, Foster C, Munford R, Schindler J. Proc. Natl. Acad. Sci. U. S. A. 2006; 103(7): 2268-2273.

Affiliation

Cancer Immunobiology Center, Aston Center, Department of Microbiology, University of Texas Southwestern Medical School, Dallas, TX 75390, USA. ellen.vitetta@utsouthwestern.edu

Copyright

(Copyright © 2006, National Academy of Sciences)

DOI

10.1073/pnas.0510893103

PMID

16461456

PMCID

PMC1413738

Abstract

Ricin, a highly potent toxin produced by castor beans, is classified by the Centers for Disease Control and Prevention as a level B biothreat because it is easily produced, readily available, and highly stable. There have been >750 cases of documented ricin intoxication in humans. There is no approved vaccine for ricin. Ricin contains a lectin-binding B chain and a ribotoxic A chain (RTA). In addition to its ribotoxic site, we have identified a separate site on RTA that is responsible for inducing vascular leak syndrome (VLS) in humans. We have generated a recombinant RTA with two amino acid substitutions that disrupt its ribotoxic site (Y80A) and its VLS-inducing site (V76M). This mutant recombinant RTA (named RiVax) was expressed and produced in Escherichia coli and purified. When RiVax was injected i.m. into mice it protected them against a ricin challenge of 10 LD50s. Preclinical studies in both mice and rabbits demonstrated that RiVax was safe. Based on these results, we have now conducted a pilot clinical trial in humans under an investigational new drug application submitted to the Food and Drug Administration. In this study, three groups of five normal volunteers were injected three times at monthly intervals with 10, 33, or 100 mug of RiVax. The vaccine was safe and elicited ricin-neutralizing Abs in one of five individuals in the low-dose group, four of five in the intermediate-dose group, and five of five in the high-dose group. These results justify further development of the vaccine.

Language: en