Development of a recombinant Leishmania major strain sensitive to ganciclovir and 5-fluorocytosine for use as a live vaccine challenge in clinical trials

Vaccine. 2005 Jan 19;23(9):1170-7. doi: 10.1016/j.vaccine.2004.08.032.


To provide a safer live challenge strain for use in clinical vaccine trials, a double drug sensitive strain of Leishmania major was derived using advances in gene targeting technology by stably introducing into the chromosome a modified HSV-1 thymidine kinase gene (tk), conferring increased sensitivity to ganciclovir (GCV), and a Saccharomyces cerevisiae cytosine deaminase gene (cd), conferring sensitivity to 5-fluorocytosine (5-FC). In vitro studies showed that the homozygous L. major (tk-cd+/+) promastigotes were killed by either drug alone, and together the drugs acted synergistically. In vivo infection studies showed that progressively growing lesions in BALB/c mice, caused by L. major (tk-cd+/+), were completely cured by 2 weeks of treatment with either drug alone or in combination. Treated animals showed no signs of reoccurrence of infection for at least 4 months when the experiments were terminated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Clinical Trials as Topic / methods*
  • Dose-Response Relationship, Drug
  • Female
  • Fluorouracil / pharmacology*
  • Ganciclovir / pharmacology*
  • Leishmania major / drug effects*
  • Leishmania major / genetics
  • Leishmaniasis, Cutaneous / genetics
  • Leishmaniasis, Cutaneous / prevention & control
  • Mice
  • Mice, Inbred BALB C
  • Protozoan Vaccines / administration & dosage*
  • Protozoan Vaccines / genetics


  • Protozoan Vaccines
  • Ganciclovir
  • Fluorouracil