The History of Live Attenuated <i>Centrin</i> Gene-Deleted <i>Leishmania</i> Vaccine Candidates
Leishmaniasis, caused by an infection of the <i>Leishmania</i> protozoa, is a neglected tropical disease and a major health problem in tropical and subtropical regions of the world, with approximately 350 million people worldwide at risk and 2 million new cases occurring annually. Curren...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
|
| Series: | Pathogens |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-0817/11/4/431 |
| _version_ | 1797444392512913408 |
|---|---|
| author | Greta Volpedo Parna Bhattacharya Sreenivas Gannavaram Thalia Pacheco-Fernandez Timur Oljuskin Ranadhir Dey Abhay R. Satoskar Hira L. Nakhasi |
| author_facet | Greta Volpedo Parna Bhattacharya Sreenivas Gannavaram Thalia Pacheco-Fernandez Timur Oljuskin Ranadhir Dey Abhay R. Satoskar Hira L. Nakhasi |
| author_sort | Greta Volpedo |
| collection | DOAJ |
| description | Leishmaniasis, caused by an infection of the <i>Leishmania</i> protozoa, is a neglected tropical disease and a major health problem in tropical and subtropical regions of the world, with approximately 350 million people worldwide at risk and 2 million new cases occurring annually. Current treatments for leishmaniasis are not highly efficacious and are associated with high costs, especially in low- and middle-income endemic countries, and high toxicity. Due to a surge in the incidence of leishmaniases worldwide, the development of new strategies such as a prophylactic vaccine has become a high priority. However, the ability of <i>Leishmania</i> to undermine immune recognition has limited our efforts to design safe and efficacious vaccines against leishmaniasis. Numerous antileishmanial vaccine preparations based on DNA, subunit, and heat-killed parasites with or without adjuvants have been tried in several animal models but very few have progressed beyond the experimental stage. However, it is known that people who recover from <i>Leishmania</i> infection can be protected lifelong against future infection, suggesting that a successful vaccine requires a controlled infection to develop immunologic memory and subsequent long-term immunity. Live attenuated <i>Leishmania</i> parasites that are non-pathogenic and provide a complete range of antigens similarly to their wild-type counterparts could evoke such memory and, thus, would be effective vaccine candidates. Our laboratory has developed several live attenuated <i>Leishmania</i> vaccines by targeted <i>centrin</i> gene disruptions either by homologous recombination or, more recently, by using genome editing technologies involving CRISPR-Cas9. In this review, we focused on the sequential history of <i>centrin</i> gene-deleted <i>Leishmania</i> vaccine development, along with the characterization of its safety and efficacy. Further, we discussed other major considerations regarding the transition of dermotropic live attenuated <i>centrin</i> gene-deleted parasites from the laboratory to human clinical trials. |
| first_indexed | 2024-03-09T13:10:59Z |
| format | Article |
| id | doaj.art-d201d59202724fbeb8f4224ef20cc379 |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-09T13:10:59Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-d201d59202724fbeb8f4224ef20cc3792023-11-30T21:42:13ZengMDPI AGPathogens2076-08172022-04-0111443110.3390/pathogens11040431The History of Live Attenuated <i>Centrin</i> Gene-Deleted <i>Leishmania</i> Vaccine CandidatesGreta Volpedo0Parna Bhattacharya1Sreenivas Gannavaram2Thalia Pacheco-Fernandez3Timur Oljuskin4Ranadhir Dey5Abhay R. Satoskar6Hira L. Nakhasi7Departments of Pathology and Microbiology, Wexner Medical Center, The Ohio State University, Columbus, OH 43201, USADivision of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USADivision of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USADepartments of Pathology and Microbiology, Wexner Medical Center, The Ohio State University, Columbus, OH 43201, USADivision of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USADivision of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USADepartments of Pathology and Microbiology, Wexner Medical Center, The Ohio State University, Columbus, OH 43201, USADivision of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USALeishmaniasis, caused by an infection of the <i>Leishmania</i> protozoa, is a neglected tropical disease and a major health problem in tropical and subtropical regions of the world, with approximately 350 million people worldwide at risk and 2 million new cases occurring annually. Current treatments for leishmaniasis are not highly efficacious and are associated with high costs, especially in low- and middle-income endemic countries, and high toxicity. Due to a surge in the incidence of leishmaniases worldwide, the development of new strategies such as a prophylactic vaccine has become a high priority. However, the ability of <i>Leishmania</i> to undermine immune recognition has limited our efforts to design safe and efficacious vaccines against leishmaniasis. Numerous antileishmanial vaccine preparations based on DNA, subunit, and heat-killed parasites with or without adjuvants have been tried in several animal models but very few have progressed beyond the experimental stage. However, it is known that people who recover from <i>Leishmania</i> infection can be protected lifelong against future infection, suggesting that a successful vaccine requires a controlled infection to develop immunologic memory and subsequent long-term immunity. Live attenuated <i>Leishmania</i> parasites that are non-pathogenic and provide a complete range of antigens similarly to their wild-type counterparts could evoke such memory and, thus, would be effective vaccine candidates. Our laboratory has developed several live attenuated <i>Leishmania</i> vaccines by targeted <i>centrin</i> gene disruptions either by homologous recombination or, more recently, by using genome editing technologies involving CRISPR-Cas9. In this review, we focused on the sequential history of <i>centrin</i> gene-deleted <i>Leishmania</i> vaccine development, along with the characterization of its safety and efficacy. Further, we discussed other major considerations regarding the transition of dermotropic live attenuated <i>centrin</i> gene-deleted parasites from the laboratory to human clinical trials.https://www.mdpi.com/2076-0817/11/4/431<i>Leishmania</i>visceral leishmaniasisvaccinelive attenuated parasite vaccinespan-<i>Leishmania</i> vaccine |
| spellingShingle | Greta Volpedo Parna Bhattacharya Sreenivas Gannavaram Thalia Pacheco-Fernandez Timur Oljuskin Ranadhir Dey Abhay R. Satoskar Hira L. Nakhasi The History of Live Attenuated <i>Centrin</i> Gene-Deleted <i>Leishmania</i> Vaccine Candidates Pathogens <i>Leishmania</i> visceral leishmaniasis vaccine live attenuated parasite vaccines pan-<i>Leishmania</i> vaccine |
| title | The History of Live Attenuated <i>Centrin</i> Gene-Deleted <i>Leishmania</i> Vaccine Candidates |
| title_full | The History of Live Attenuated <i>Centrin</i> Gene-Deleted <i>Leishmania</i> Vaccine Candidates |
| title_fullStr | The History of Live Attenuated <i>Centrin</i> Gene-Deleted <i>Leishmania</i> Vaccine Candidates |
| title_full_unstemmed | The History of Live Attenuated <i>Centrin</i> Gene-Deleted <i>Leishmania</i> Vaccine Candidates |
| title_short | The History of Live Attenuated <i>Centrin</i> Gene-Deleted <i>Leishmania</i> Vaccine Candidates |
| title_sort | history of live attenuated i centrin i gene deleted i leishmania i vaccine candidates |
| topic | <i>Leishmania</i> visceral leishmaniasis vaccine live attenuated parasite vaccines pan-<i>Leishmania</i> vaccine |
| url | https://www.mdpi.com/2076-0817/11/4/431 |
| work_keys_str_mv | AT gretavolpedo thehistoryofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT parnabhattacharya thehistoryofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT sreenivasgannavaram thehistoryofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT thaliapachecofernandez thehistoryofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT timuroljuskin thehistoryofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT ranadhirdey thehistoryofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT abhayrsatoskar thehistoryofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT hiralnakhasi thehistoryofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT gretavolpedo historyofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT parnabhattacharya historyofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT sreenivasgannavaram historyofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT thaliapachecofernandez historyofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT timuroljuskin historyofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT ranadhirdey historyofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT abhayrsatoskar historyofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates AT hiralnakhasi historyofliveattenuatedicentrinigenedeletedileishmaniaivaccinecandidates |