Leishmaniasis is one of the six major tropical diseases identified by the World Health Organization for intense further study. It is caused by infection with the protozoan parasite, Leishmania, following a bite by an infected sandfly. The disease is prevalent in six continents and considered endemic in 88 countries. More than 2 million new cases are reported annually, with a worldwide prevalence of 12 million people and a population of over 350 million at risk. However, at present there is no vaccine for human Leishmaniasis. We have discovered that attenuated Leishmania major parasites (called LPG2 KO) can provide outstanding protection against this disease in a mouse model. These parasites are deficient in the gene necessary for the transport of GDP-mannose into the Golgi, a critical event required for the assembly of the disaccharide-phosphate repeats of lipophosphoglycan (LPG) and other glycophosphate conjugates associated with Leishmania. Importantly, LPG2 KO parasites fail to initiate disease, but are maintained long-term in mice at low levels. In anticipation of vaccine trials in non-human primates, we seek to characterize the attributes of the vaccine-induced immunity that we obtain with these parasites. Toward that end, we will study LPG2 KO immunized mice to define the initial immune response associated with vaccination (Aim 1), characterize the memory T cell responses that develop (Aim 2), and determine if adjuvants enhance the protective immunity induced by these parasites (Aim 3). These studies will address important issues of vaccine development, including the role of vaccine dose and host genetic background, and will hopefully provide better correlates of immunity for leishmaniasis. In addition, these studies will provide basic information about memory T cell generation that should be useful in developing vaccines that require cell-mediated immunity. Overall, these experiments will establish the parameters for using LPG2 KO parasites as a vaccine in non-human primates, and provide basic information of wider importance in developing a leishmanial vaccine. ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VACC (04))
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MO, Annie X Y
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University of Pennsylvania
Schools of Veterinary Medicine
United States
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