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Development of a safe live Leishmania vaccine line by gene replacement.
Open accessAbstract
Vaccination with live Leishmania major has been shown to yield effective immunization in humans; however, this has been discontinued because of problems associated with virulence of the available vaccine lines. To circumvent this, we tested the ability of a dhfr-ts- null mutant of L. major, obtained by gene targeting, to infect and then to vaccinate mice against challenge with virulent L. major. Survival and replication of dhfr-ts- in macrophages in vitro were dependent upon thymidine, with parasites differentiating into amastigotes prior to destruction. dhfr-ts- parasites persisted in BALB/c mice for up to 2 months, declining with a half-life of 2-3 days. Nonetheless, dhfr-ts- was incapable of causing disease in both susceptible and immunodeficient (nu/nu) BALB/c mice. Animal infectivity could be partially restored by thymidine supplementation. When inoculated by the i.v., s.c., or i.m. routes into mice, dhfr-ts- could elicit substantial resistance to a subsequent challenge with virulent L. major. Thus, Leishmania bearing auxotrophic gene knockouts can be safe and induce protective immunity. Potentially, dhfr-ts- could be used as a platform for delivery of immunogens relevant to other diseases.
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Citations
Cited by
Leishmaniasis: Current Status of Vaccine Development
Handman, E. (2001) · Clinical Microbiology Reviews · doi:10.1128/cmr.14.2.229-243.2001 · Cited by 600
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Agüero, F., Al-Lazikani, B., Aslett, M., Berriman, M., Buckner, F. S., Campbell, R. K., Carmona, S., Carruthers, I. M., Chan, A. W. E., Chen, F., et al. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2684 · Cited by 306
Späth, G. F., Epstein, L., Leader, B., Singer, S. M., Avila, H. A., Turco, S. J., & Beverley, S. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.160257897 · Cited by 301
Self-citationLeishmaniasis vaccine: Where are we today?
Kedzierski, L. (2010) · Journal of Global Infectious Diseases · doi:10.4103/0974-777x.62881 · Cited by 202
Persistence Without Pathology in Phosphoglycan-Deficient Leishmania major
Späth, G. F., Lye, L.-F., Segawa, H., Sacks, D. L., Turco, S. J., & Beverley, S. M. (2003) · Science · doi:10.1126/science.1087499 · Cited by 167
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Metadata
- Authors
- Titus, R. G., Gueiros-Filho, F. J., de Freitas, L. A., & Beverley, S. M.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1995-10-24
- Volume
- 92
- Issue
- 22
- Pages
- 10267-10271
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2060098125
- Cited by
- 228
- References
- 0
- FWCI
- 11.15
- Type
- journal article
- Language
- en
- Open access
- green
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- Titus, R. G., Gueiros-Filho, F. J., de Freitas, L. A., & Beverley, S. M. (1995). Development of a safe live Leishmania vaccine line by gene replacement. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.92.22.10267
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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