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

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.

• Authors: 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
• Journal: Communications biology (Commun Biol) Vol. 4 Issue 1 Pg. 929 (07 30 2021) ISSN: 2399-3642 [Electronic] England
• PMID: 34330999 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: © 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Chemical References

• Leishmaniasis Vaccines
• Protozoan Proteins
• Vaccines, Attenuated

Topics

• Gene Deletion
• Genes, Protozoan
• Leishmania donovani (genetics, immunology)
• Leishmaniasis Vaccines (immunology)
• Leishmaniasis, Visceral (immunology, prevention & control)
• Protozoan Proteins
• Vaccines, Attenuated (immunology)