Preclinical validation of a live attenuated dermotropic Leishmania vaccine against vector transmitted fatal visceral leishmaniasis

Subir Karmakar; Nevien Ismail; Fabiano Oliveira; James Oristian; Wen Wei Zhang; Swarnendu Kaviraj; Kamaleshwar P Singh; Abhishek Mondal; Sushmita Das; Krishna Pandey; Parna Bhattacharya; Greta Volpedo; Sreenivas Gannavaram; Monika Satoskar; Sanika Satoskar; Rajiv M Sastry; Timur Oljuskin; Telly Sepahpour; Claudio Meneses; Shinjiro Hamano; Pradeep Das; Greg Matlashewski; Sanjay Singh; Shaden Kamhawi; Ranadhir Dey; Jesus G Valenzuela; Abhay Satoskar; Hira L Nakhasi

doi:10.1038/s42003-021-02446-x

Preclinical validation of a live attenuated dermotropic Leishmania vaccine against vector transmitted fatal visceral leishmaniasis

Commun Biol. 2021 Jul 30;4(1):929. doi: 10.1038/s42003-021-02446-x.

Authors

Subir Karmakar¹, Nevien Ismail¹, Fabiano Oliveira², James Oristian², Wen Wei Zhang³, Swarnendu Kaviraj⁴, Kamaleshwar P Singh⁴, Abhishek Mondal⁵, Sushmita Das⁵, Krishna Pandey⁵, Parna Bhattacharya¹, Greta Volpedo⁶, Sreenivas Gannavaram¹, Monika Satoskar¹, Sanika Satoskar¹, Rajiv M Sastry¹, Timur Oljuskin¹, Telly Sepahpour¹, Claudio Meneses², Shinjiro Hamano^{7

8}, Pradeep Das⁵, Greg Matlashewski⁹, Sanjay Singh¹⁰, Shaden Kamhawi¹¹, Ranadhir Dey¹², Jesus G Valenzuela¹³, Abhay Satoskar¹⁴, Hira L Nakhasi¹⁵

Affiliations

¹ Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA.
² Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA.
³ Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
⁴ Gennova Biopharmaceuticals, Hinjawadi Phase II, Pune, Maharashtra, India.
⁵ Rajendra Memorial Research Institute of Medical Sciences, Patna, India.
⁶ Department of Pathology and Microbiology, Ohio State University, Columbus, OH, USA.
⁷ Department of Parasitology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
⁸ The Joint Usage/Research Center on Tropical Disease, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
⁹ Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada. greg.matlashewski@mcgill.ca.
¹⁰ Gennova Biopharmaceuticals, Hinjawadi Phase II, Pune, Maharashtra, India. Sanjay.Singh@gennova.co.in.
¹¹ Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA. skamhawi@niaid.nih.gov.
¹² Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA. Ranadhir.Dey@fda.hhs.gov.
¹³ Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA. jvalenzuela@niaid.nih.gov.
¹⁴ Department of Pathology and Microbiology, Ohio State University, Columbus, OH, USA. Abhay.Satoskar@osumc.edu.
¹⁵ Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA. Hira.Nakhasi@fda.hhs.gov.

Abstract

Visceral Leishmaniasis (VL), a potentially fatal disease is caused by Leishmania donovani parasites with no vaccine available. Here we produced a dermotropic live attenuated centrin gene deleted Leishmania major (LmCen^-/-) vaccine under Good Laboratory Practices and demonstrated that a single intradermal injection confers robust and durable protection against lethal VL transmitted naturally via bites of L. donovani-infected sand flies and prevents mortality. Surprisingly, immunogenicity characteristics of LmCen^-/- parasites revealed activation of common immune pathways like L. major wild type parasites. Spleen cells from LmCen^-/- immunized and L. donovani challenged hamsters produced significantly higher Th1-associated cytokines including IFN-γ, TNF-α, and reduced expression of the anti-inflammatory cytokines like IL-10, IL-21, compared to non-immunized challenged animals. PBMCs, isolated from healthy people from non-endemic region, upon LmCen^-/- infection also induced more IFN-γ compared to IL-10, consistent with our immunogenicity data in LmCen^-/- immunized hamsters. This study demonstrates that the LmCen^-/- parasites are safe and efficacious against VL and is a strong candidate vaccine to be tested in a human clinical trial.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Gene Deletion*
Genes, Protozoan*
Leishmania donovani / genetics
Leishmania donovani / immunology*
Leishmaniasis Vaccines / immunology*
Leishmaniasis, Visceral / immunology
Leishmaniasis, Visceral / prevention & control*
Protozoan Proteins
Vaccines, Attenuated / immunology

Substances

Leishmaniasis Vaccines
Protozoan Proteins
Vaccines, Attenuated

Grants and funding

CIHR/Canada