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Publishable summary

1.1 Context

Leishmaniasis has been categorized by the World Health Organization as a “re-emerging and uncontrolled disease”, having detrimental effects on the development of endemic countries.
Various drugs (usually quite expensive) are currently being employed, which raises the problem of the development of resistance. On the other hand, vaccination is expected to be more cost-effective mean and can reach the goal of global control and/or eradication of the parasite infection. But, no such vaccine is available today.
Furthermore, tools enabling the precise categorization of the target population are also missing. As a consequence, it is still impossible to detect the individuals who should be vaccinated, and those who should not because of natural immunisation (innate or acquired immunity).

1.2 Objectives of the project

RAPSODI will first develop a human vaccine candidate based on a crude excreted-secreted antigen obtained from promastigote culture supernatant of Leishmania infantum, which gave highly promising results on dogs, a natural reservoir of visceral leishmaniasis (the more severe form). RAPSODI will also investigate the possibility of extending the action of the vaccine candidate to cutaneous and mucocutaneous leishmaniasis. At the end of the project, the vaccine candidate should be ready for human clinical trials.
RAPSODI will also develop assays for population categorization, together with a marker signature for genetic susceptibility assessment. Finally, RAPSODI will provide the immunoassay associated to the efficiency follow-up of vaccination.

1.3 Work performed and results obtained

The project workplan is globally divided in three axes: i) the vaccine candidate definition and production; ii) testing the antigens on human cells and the vaccine candidates on animals and iii) the setting-up of a toolbox for unraveling the specific features (parasitological, immunological and genetic) of resistance. Transversally, the recruitment of individuals from various conditions is needed to feed the project with appropriate and documented samples. The overall results should lead to an operable vaccine candidate and the related protocols for the qualification and follow-up of patients to vaccination.
  
Vaccine candidate antigens were produced under GMP standards. These antigens were distributed among partners for the toolbox setting-up on patient samples. In parallel, the formulation into vaccine candidates and their related analysis are in progress.

As the vaccine antigens are not strictly defined once and for all yet, all preliminary testing was possible, but the results are promising.

Regarding the definition of parasitological features of resistance, the goal of applying the same PCR approach to detect and quantify Leishmania infection within RAPSODI project, and make this comparable among partners, was achieved; more work aiming at identifying the parasitic load threshold for asymptomatic and symptomatic individuals and identifying the causative species of leishmaniasis is on-going.
Concerning the definition of immunological markers of resistance, an ELISA assay to determine plasma levels of different human immunoglobulin isotypes specific for Leishmania antigens is about to be finalized. This test will be to evaluate efficient vaccination and to discriminate vaccinated from infected individuals. In parallel, studies on the cell mediated immunity to Leishmania infection are on-going.
As far as genetic features are concerned, contrasting macrophage infection phenotypes were evidenced on limited human samples, validating the proposed experimental approach. A robust and useful macrophage infection micro assay adapted to small field blood samples is now ready to use.

Apart from legal requirements (namely ethical clearance), the patient recruitment procedure needed to be standardized among the various population and phenotypes. An important work aiming at defining precise and common inclusion/exclusion criteria was performed; also, VL, CL and ML diagnostic methods and epidemiological, clinical, parasitological and immunological criteria were clearly established and standardized. The resulting protocols should be soon made available to the scientific community. A common procedure of sample handling was also designed and training sessions were organized within the consortium in order to avoid discrepancies related to manipulation bias. 

The next steps will seek for gathering more comprehensive data on the efficiency of vaccine antigens and candidates on the relevant in vivo models, and finalize the conclusion of the definition of features of resistance.

1.4 Potential impact and use

Leishmaniasis is affecting 88 endemic countries with a potential of 360 Mo individuals at risk; its annual incidence is close to 2 Mo individuals, while its prevalence accounts for 14 Mo individuals; approximately 59 000 patients are dying each year. By developing solutions to circumvent such a “re-emerging and uncontrolled disease”, the vaccine candidate issued from RAPSODI shall have a great impact on the development of endemic countries, and improve the quality of life of their inhabitants by limiting social and health burdens. In addition, and quite independently from the vaccine development itself, the categorization tests will be very useful to enhance epidemiological data from the endemic areas, and could be useful to whatever clinical trials. Finally, the standardization and training activities will help enhancing a common view of dealing with leishmaniasis-related issues among the scientific community.

In order to promote the project results among the scientific community but also among the population whose life is at stake, a website has been set up (www.fp7-rapsodi.eu). A logo was also created, together with an introducing booklet and a general graphical charter, in order to provide a distinguishable identity.

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