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RFP Year2018
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Awarded Amount$3,998,989DiseaseNTD(Leishmaniasis)InterventionVaccineDevelopment StageLead OptimizationCollaboration PartnersInstitute of Tropical Medicine (NEKKEN) Nagasaki University , Gennova Biopharmaceuticals Ltd. , McGill University , The Ohio State UniversityPast ProjectPublication
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Zhang WW, Karmakar S, Gannavaram S, Dey R, Lypaczewski P, Ismail N, Siddiqui A, Simonyan V, Oliveira F, Coutinho-Abreu IV, DeSouza-Vieira T, Meneses C, Oristian J, Serafim TD, Musa A, Nakamura R, Saljoughian N, Volpedo G, Satoskar M, Satoskar S, Dagur PK, McCoy JP, Kamhawi S, Valenzuela JG, Hamano S, Satoskar AR, Matlashewski G, Nakhasi HL. A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing. Nat Commun. 2020 Jul 10;11(1):3461. doi: 10.1038/s41467-020-17154-z. PMID: 32651371; PMCID: PMC7351751.
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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. 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. PMID: 34330999 PMCID: PMC8324786
Introduction and Background of the Project
Introduction
The leishmaniases comprise a number of diseases caused by obligate intracellular parasites of the genus Leishmania that is transmitted by the bites of infected sandflies. With over 350 million people worldwide at risk of contracting leishmaniasis, the WHO classifies leishmaniasis as a neglected tropical disease. Visceral leishmaniasis (VL) is the most severe form of the disease which is fatal without treatment. It is well documented that patients who recover from leishmaniasis including VL develop protective immunity against reinfection, which altogether indicates that a vaccine is feasible. Our team has developed a live attenuated vaccine for leishmaniasis by generating an attenuated dermotropic Leishmania by deleting a key gene to be critical for parasite virulence and persistence in the host.
Project objective
The overall objective of this project is to advance the preclinical development of this vaccine candidate. The aims of this project are: 1) Undertake pre-clinical toxicology studies on the vaccine as per regulatory guidelines, 2) Manufacture clinical grade GMP vaccine for clinical trials.
Project design
Using CRISPR-Cas technology, we have successfully generated antibiotic selection marker free centrin gene deficient L. major (LmCen-/-) and have established their safety and efficacy in pre-clinical laboratory studies. Our team will produce LmCen-/- vaccine under GLP conditions, undertake pre-clinical toxicology testing in animals as per regulatory guidelines and manufacture sufficient quantities of clinical grade GMP LmCen-/- for clinical testing.
How can your partnership (project) address global health challenges?
No licensed human vaccine is currently available for leishmaniasis. The Ohio State University with its partners Nagasaki University, McGill University, Gennova Biopharmaceuticals have developed a live attenuated vaccine against leishmaniasis. This project will further advance pre-clinical development of this vaccine candidate for human trials and will lead to a safe, affordable and effective vaccine against all forms of leishmaniasis. If successful, this vaccine can help reduce the global burden of leishmaniasis and achieve disease elimination.
What sort of innovation are you bringing in your project?
This is the first vaccine for leishmaniasis developed by generating a novel attenuated cutaneous disease causing species, centrin gene deficient L. major (LmCen-/-) using CRISPR-Cas technology. CRISPR-Cas enabled the development of attenuated strains as a defined product without antibiotic resistance genes and off target mutations that can advance to human trials.
Role and Responsibility of Each Partner
Gennova Biopharmaceuticals will produce LmCen-/- vaccine for clinical trials. The Ohio State University and Nagasaki University will evaluate the safety of LmCen-/- vaccine, and Nagasaki University will perform toxicology studies on LmCen-/- product manufactured by Gennova. McGill University will undertake genomic characterization of LmCen-/- vaccine. Scientists at US-FDA and NIAID/NIH will evaluate the efficacy of industry manufactured vaccine using select animal models of CL and VL. All partners will be involved in compiling documents for submission to regulatory authorities.
Final Report
1. Project objective:
The overarching goal of this current project is to establish GLP and cGMP manufacturing of LmCen-/- in serum free conditions and undertake the preclinical development of the LmCen-/- candidate as a live attenuated vaccine for leishmaniasis. The development of a marker free attenuated Leishmania strain, for the first time opens the pathway to performing human clinical trials.
2. Project design:
- ・ Produce GLP grade Animal Component Free (ACF) centrin gene deficient Leishmania major (ACF-LmCen-/-) material as a live attenuated vaccine candidate for leishmaniasis
- ・ Undertake preclinical characterization, toxicology and safety studies of GLP grade ACF-LmCen-/- in animal models as per US-FDA guidance
- ・ Produce cGMP grade ACF-LmCen-/- material for clinical trials
- ・ Complete pre-investigational new drug (pre-IND) meetings with regulators and identify partners and clinical sites for phase I safety studies
3. Results, lessons learned:
A well characterized cGMP cell bank of LmCen-/- promastigotes was prepared by ATCC for cGMP production at Gennova Biopharmaceuticals. All conditions, batch release criteria and scalable process for growing LmCen-/- in bioreactor was developed and optimized by Gennova Biopharmaceuticals. Required approvals were secured from regulators in India for commencing cGMP production of the LmCen-/- vaccine. Safety and efficacy of bioreactor grown GLP grade LmCen-/- produced at Gennova was tested in animal models of cutaneous and visceral leishmaniasis in two different laboratories. Long-term stability of LmCen-/- vaccine under LN2 storage condition was evaluated and was found to be at least 2 years. Immunogenicity of LmCen-/- parasites was demonstrated in preclinical animal models by measuring protective cytokines and chemokines and by IFN-γ and IL-10 production from LmCen-/--stimulated PBMCs from healthy individuals. These studies determined that LmCen-/- induced strong multifunctional T cells response in animal models and a higher IFN-γ/IL-10 ratio in healthy controls. Preclinical toxicology studies were performed in rats as per US-FDA regulatory guidelines using cGMP LmCen-/- produced in engineering production runs. These studies demonstrated that the vaccine was safe and immunogenic in rats. We also conducted compatibility test of the intradermal injection device from Terumo, Japan to be used in the Phase I studies in preclinical animal models. We have submitted all the relevant documents for PreIND meeting with the US Food and Drug Administration in preparation for filing IND to conduct Phase I studies using cGMP LmCen-/- vaccine. The meeting was taken place in November 2024. In addition to the phase I trials to be undertaken in the USA, multiple potential sites for clinical trials were visited in several endemic countries. Two GCP compliant sites KEMRI-Kericho-Kenya and UFMG, Brazil were selected for undertaking Phase I clinical trials.
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Live attenuated prophylactic vaccine for leishmaniasis