Visceral leishmaniasis (VL), a vector borne disease caused by protozoan parasites of the genus Leishmania, is responsible for significant morbidity and mortality worldwide and constitutes a major public health problem particularly in poorer countries. There is also recognised risk that the disease may become more prevalent in Europe as a consequence of global warming and migration. Treatment is prolonged and expensive and has been complicated by the emergence of drug resistant Leishmania. While attempts to develop an effective vaccine have been shown to be feasible, there is no vaccine in active clinical use. The past decade has seen increasing interest in the use of dietary lactic acid bacteria (LAB) as mucosal vaccine delivery vehicles and a number of prototypes have demonstrated efficacy in experimental models of infectious diseases. Furthermore, some strains of LAB have been shown to promote T helper 1 or mixed T helper (Th) cellular responses to expressed or co-administered antigen, which are considered advantageous in vaccination strategies targeting VL. The goal of this proposal is therefore to develop a new immuno-prophylactic paradigm for preventing VL. We will bioengineer harmless Lactococcus lactis (an LAB) to express conserved immunogenic antigens from Leishmania infantum, the causative agent of VL in Europe. Using animal models, we will demonstrate that these bioengineered strains can prevent disease after parasitic challenge when administered as a mucosal vaccine. We will also test the properties of a L. lactis strain producing interleukin-12 (a potent cytokine that induces Th1 cells) when co-administered as a mucosal adjuvant. If successful, this program of research has enormous potential to create a new path to preventing VL disease and other leishmaniases that is both inexpensive and amenable to large-scale vaccination programmes in populations who are at risk. There may also be scope to expand this approach to target other neglected diseases.
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