LABVLEISH · MUCOSAL VACCINATION USING NON-PATHOGENIC LACTIC ACID BACTERIA AS A STRATEGY TO PREVENT MORBIDITY AND MORTALITY CAUSED BY VISCERAL LEISHMANIASIS

mucosal vaccination using non-pathogenic lactic acid bacteria as a strategy to prevent morbidity and mortality caused by visceral leishmaniasis

Project context and objectives isceral 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. It is endemic in 88 countries including large areas of the tropics, subtropics and Mediterranean basin, effecting 12 million people worldwide and threatening a further 350 million people with 2 million new cases and at least 60 000 deaths (mainly children and young adults) annually. There is also a recognised risk that the disease may become more prevalent in Europe as a consequence of global warming and/or migration, and recent reports of indigenous VL cases in Northern Italy and southern Germany indicate that autochthonous leishmaniasis is spreading northwards. Asymptomatic infections may also be more widespread and pose a significant threat as they can progress to severe clinical forms in immunocompromised individuals, as seen previously with the rapid rise of leishmaniasis in HIV patients in the 1990s. Moreover, the etiologic agent of southern European VL (Leishmania infantum) also infects dogs which thus constitute the major reservoir for the parasite and a major risk to humans. Treatment strategies are both prolonged and expensive and have been complicated by the emergence of drug-resistant Leishmania strains. While attempts to develop an effective vaccine have been shown to be feasible, there is currently no vaccine in active clinical use. In FP7, as part of "its objective to improve the health of European citizens, boost the competitiveness of health-related industries and businesses, and address global health issues", the EC recognised the need to work more closely with the WHO in order to prioritise a R&D agenda to define needs and priorities for the developing world. It is this key aspect and in particular the call to "develop a safe and efficient vaccine generating a broadly protecting immune response against different Leishmania species in particular those responsible for Visceral Leishmaniasis" that formed the background to the project described here. This project set out to provide a basis for a new immuno-prophylactic strategy for preventing morbidity and mortality caused by VL, which uses dietary lactic acid bacteria (LAB) as mucosal deliver vehicles. There has been increasing interest in the use of 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 project was therefore to test the hypothesis that lactococcal strains bioengineered to express Leishmania antigens can provide protective efficacy in animal models of VL when administered as a mucosal vaccine. Project results In the first year of the project, we focused on the development of LAB vaccine strain prototypes expressing the model Leishmania antigens, Kmp11 (Kinetoplast membrane protein 11) and PSA (Promastigote Surface Antigen). These antigens were selected as they have demonstrated protective efficacy (as protein or DNA based vaccines) in animal models of leishmaniasis and/or been shown to induce Th1 type cellular responses in patients (either cured or infected with Leishmania) and experimental models of VL [11-12]. PSA is also currently being tested in the host laboratory as a vaccine candidate for use against visceral and tegumentary forms of leishmaniases in humans, as part of the FP7-funded RAPSODI project - see http://www.fp7-rapsodi.eu/ for more information. As these proteins are also highly conserved between species, they may be capable of "generating a broadly protecting immune response against different Leishmania species". Various vaccine prototypes were bioengineered to express these antigens in different cellular compartments. In addition, a strain producing and secreting murine IL-12 was also developed to use as a mucosal adjuvant to enhance antigen-specific cellular responses (Th1-type) in vivo when co-administered with the aforementioned vaccines. In the second year of the project, following preliminary testing, the vaccine prototypes were tested as mucosal vaccines for their immunogenicity and efficacy in an experimental mouse model of Visceral leishmaniasis. The tested prototypes were observed to confer a level of protection (reduction in parasitemia) comparable to that obtained with purified antigen administered by injection with adjuvant. Moreover, these reductions in parasitemia were associated with distinct antigen-specific cellular cytokine response profiles. This research programme has formed an excellent basis for the development of novel adjuvants and further studies aimed at creating a new path to preventing VL disease and other leishmaniases that is both inexpensive and amenable to large-scale vaccination programmes in populations at risk. There may also be scope to expand this approach to target other neglected diseases. Project impact Enhancement of competence and skill diversification, encompassing parasitology and immunology, acquired during this research training and career development programme should support Dr Hanniffy's efforts to attain an independent position as leader of a multi-disciplinary team carrying out innovative research in the European research environment as part of a structured and long-term development programme. He will also benefit from links established whilst at ISCIII, both with industry and researchers from across Europe and third countries. Meanwhile, key knowledge that has been transferred to the host institution, Instituto de Salud, Carlos III (and the WHO collaborating laboratory for Leishmaniasis), will enable it to consolidate its position as a leading centre for collaborative research in this field. Moreover, it is intended that this project will form the basis for establishing a durable collaboration between the beneficiary and host institution which should further promote links between European researchers in different countries.

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