Leishmaniasis is a protozoan parasitic disease endemic to the tropical and subtropical regions of the world, with three major clinical forms, self-healing cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL). Drug treatments are expensive and often result in the development of drug resistance. No vaccine is available against leishmaniasis. Subunit Leishmania vaccine immunization in animal models has shown some efficacy but little or none in humans. However, individuals who recover from natural infection are protected from reinfection and develop life-long protection, suggesting that infection may be a prerequisite for immunological memory. Thus, genetically altered live-attenuated parasites with controlled infectivity could achieve such memory. In this paper, we discuss development and characteristics of genetically altered, live-attenuated Leishmania donovani parasites and their possible use as vaccine candidates against VL. In addition, we discuss the challenges and other considerations in the use of live-attenuated parasites. 1. Introduction Leishmaniasis is caused by protozoan parasites of the genus Leishmania of the family Trypanosomatidae and is transmitted by the sand fly vector. It infects about 12 million individuals globally in tropical and subtropical regions, with ~2 million new clinical cases (0.5 million visceral leishmaniasis (VL) and 1.5 million cutaneous leishmaniasis (CL)) reported annually with an estimated death toll of ~50,000 persons/year [1]. The three major clinical forms of leishmaniasis, VL, CL, and MCL are the result of infection by different species of the parasite and the immune response of the host. VL, fatal if not treated, is caused by L. donovani, L. infantum, and L. chagasi [2, 3]. More than 90% of the visceral cases in the world are reported from Bangladesh, Brazil, India, and Sudan. Most affected patients (70%) are children under 15 years of age who already suffer from concurrent malnutrition and other secondary illnesses. The major clinical symptoms for VL are characterized by prolonged and irregular fever, splenomegaly, and hepatomegaly [3]. CL causes lesions that are self-healing and are caused by L. major, L. tropica, or L. aethiopica in the old world and by L. mexicana or L. braziliensis complex in the new world [4]. MCL is potentially life threatening and affects the mucosal region of infected individuals, typically seen in the Central and South America and caused by L. braziliensis, L. amazonensis, L. panamensis, and L. guyanensis [3]. In the Leishmania life cycle,
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