Title

A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing

Authors

Wen Wei Zhang, McGill University
Subir Karmakar, Food and Drug Administration
Sreenivas Gannavaram, Food and Drug Administration
Ranadhir Dey, Food and Drug Administration
Patrick Lypaczewski, McGill University
Nevien Ismail, Food and Drug Administration
Abid Siddiqui, Food and Drug Administration
Vahan Simonyan, Food and Drug Administration
Fabiano Oliveira, National Institute of Allergy and Infectious Diseases (NIAID)
Iliano V. Coutinho-Abreu, National Institute of Allergy and Infectious Diseases (NIAID)
Thiago DeSouza-Vieira, National Institute of Allergy and Infectious Diseases (NIAID)
Claudio Meneses, National Institute of Allergy and Infectious Diseases (NIAID)
James Oristian, National Institute of Allergy and Infectious Diseases (NIAID)
Tiago D. Serafim, National Institute of Allergy and Infectious Diseases (NIAID)
Abu Musa, Graduate School of Biomedical Sciences
Risa Nakamura, Graduate School of Biomedical Sciences
Noushin Saljoughian, The Ohio State University
Greta Volpedo, The Ohio State University
Monika Satoskar, Food and Drug Administration
Sanika Satoskar, Food and Drug Administration
Pradeep K. Dagur, National Heart, Lung, and Blood Institute (NHLBI)
J. Philip McCoy, National Heart, Lung, and Blood Institute (NHLBI)
Shaden Kamhawi, National Institute of Allergy and Infectious Diseases (NIAID)
Jesus G. Valenzuela, National Institute of Allergy and Infectious Diseases (NIAID)
Shinjiro Hamano, Graduate School of Biomedical Sciences
Abhay R. Satoskar, The Ohio State University
Greg Matlashewski, McGill University
Hira L. Nakhasi, Food and Drug Administration

Document Type

Journal Article

Publication Date

12-1-2020

Journal

Nature Communications

Volume

11

Issue

1

DOI

10.1038/s41467-020-17154-z

Abstract

© 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply. Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa transmitted by infected sand flies. Vaccination through leishmanization with live Leishmania major has been used successfully but is no longer practiced because it resulted in occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain (LmCen−/−). Notably, LmCen−/− is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen−/− have no visible lesions following challenge with L. major-infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen−/− immunization results in protection and an immune response comparable to leishmanization. LmCen−/− is safe since it is unable to cause disease in immunocompromised mice, induces robust host protection against vector sand fly challenge and because it is marker free, can be advanced to human vaccine trials.

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