Development of a live attenuated vaccine for leishmaniasis using CRISPR technology
Methods of production and use of modified Leishmania species and compositions of live, attenuated organisms, immunogenic compositions, vaccines, and pharmaceutical compositions.
Leishmaniasis is a neglected tropical disease caused by infection with protozoans of the 15 genus Leishmania that is transmitted by infected sand flies. Worldwide, an estimated 1 billion people are at risk of infection in tropical and subtropical countries, with up to 1.7 million new cases in 98 countries occurring each year and 50,000 deaths per year. The disease pathology ranges from localized skin ulcers (cutaneous leishmaniasis, CL) to fatal systemic disease (visceral leishmaniasis, VL), depending on the species of the infecting Leishmania parasite. Treatment options for leishmaniasis are very limited, and there is poor surveillance in the most highly endemic countries. Unlike most parasitic infections, patients who recover from leishmaniasis naturally or following drug treatment develop immunity against re-infection, indicating that the development of an effective vaccine should be feasible. Furthermore, leishmanization is a process in which deliberate infections with a low dose of virulent Leishmania major provides greater than 90% protection against reinfection. However, leishmanization is no longer practiced due to the resulting skin lesions that last for months at the site of inoculation and as a result, there is no best plan of treatment for leishmaniasis.
A team consisting of Abhay Satoskar (The Ohio State University), Hira Nakhasi (U.S. Food and Drug Administration), and Greg Matlashewski (McGill University) have developed a novel method of production and use of live, attenuated organisms that include a modified Leishmania species. The application of this prophylactic vaccine is for protection against leishmaniasis in which it greatly reduces transmission and supports elimination of this disease. This leishmanization vaccine is a CRISPR genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Based on mouse studies, the researchers have found that this novel markerless vaccine was safe and induced protection against sand fly transmitted Leishmania major. This combination of old (leishmanization) and new (CRISPR gene editing) technologies can result in major advances in vaccine design that has the potential to protect millions of people from this major neglected disease, especially those in developing countries, such as Africa and Asia, and those who travel to these places.