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

Wen-Wei Zhang, Subir Karmakar, Sreenivas Gannavaram, Ranadhir Dey, Patrick Lypaczewski, Nevien Ismail, Abid Siddiqui, Vahan Simonyan, Fabiano Oliveira, Iliano V. Coutinho-Abreu, Thiago DeSouza-Vieira, Claudio Meneses, James Oristian, Tiago D. Serafim, Abu Musa, Risa Nakamura, Noushin Saljoughian, Greta Volpedo, Monika Satoskar, Sanika Satoskar, Pradeep K. Dagur, J. Philip McCoy, Shaden Kamhawi, Jesus G. Valenzuela, Shinjiro Hamano, Abhay R. Satoskar (), Greg Matlashewski () and Hira L. Nakhasi ()
Additional contact information
Wen-Wei Zhang: McGill University
Subir Karmakar: Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA
Sreenivas Gannavaram: Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA
Ranadhir Dey: Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA
Patrick Lypaczewski: McGill University
Nevien Ismail: Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA
Abid Siddiqui: Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA
Vahan Simonyan: Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA
Fabiano Oliveira: Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Iliano V. Coutinho-Abreu: Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Thiago DeSouza-Vieira: Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Claudio Meneses: Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
James Oristian: Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Tiago D. Serafim: Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Abu Musa: Nagasaki University, Nagasaki, Japan and Nagasaki University Graduate School of Biomedical Sciences Doctoral Leadership Program
Risa Nakamura: Nagasaki University, Nagasaki, Japan and Nagasaki University Graduate School of Biomedical Sciences Doctoral Leadership Program
Noushin Saljoughian: Ohio State University
Greta Volpedo: Ohio State University
Monika Satoskar: Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA
Sanika Satoskar: Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA
Pradeep K. Dagur: National Institute of Heart, Lung and Blood Institute, NIH
J. Philip McCoy: National Institute of Heart, Lung and Blood Institute, NIH
Shaden Kamhawi: Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jesus G. Valenzuela: Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Shinjiro Hamano: Nagasaki University, Nagasaki, Japan and Nagasaki University Graduate School of Biomedical Sciences Doctoral Leadership Program
Abhay R. Satoskar: Ohio State University
Greg Matlashewski: McGill University
Hira L. Nakhasi: Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17154-z

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