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Development of a Multi-Epitope Peptide Vaccine Against Human Leishmaniases Joana Da Silva Pissarra

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Development of a Multi-Epitope Peptide Vaccine Against Human Leishmaniases Joana Da Silva Pissarra Development of a multi-epitope peptide vaccine against human leishmaniases Joana da Silva Pissarra To cite this version: Joana da Silva Pissarra. Development of a multi-epitope peptide vaccine against human leishmaniases. Human health and pathology. Université Montpellier, 2019. English. NNT : 2019MONTT013. tel- 02387247 HAL Id: tel-02387247 https://tel.archives-ouvertes.fr/tel-02387247 Submitted on 29 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE POUR OBTENIR LE GRADE DE DOCTEUR DE L’UNIVERSITÉ DE M ONTPELLIER En Biologie Santé École Doctorale Sciences Chimiques et Biologiques pour la Santé Unité de recherche UMR177 INTERTRYP – Institut de Recherche pour le Développement (IRD) Development of a multi-epitope peptide vacc ine against human leishmaniases Présentée par Joana PISSARRA Le 26 Juin 2019 Sous la direction du Dr. Jean-Loup LEMESRE Devant le jury composé de Bernard MAILLÈRE, Dr., CEA-Saclay Président / Examinateur Claude LECLERC, Pr., Institut Pasteur Paris Rapporteur Sylviane PIED, Dr., Institut Pasteur Lille Rapporteur Nicolas BLANCHARD, Dr., Université de Toulouse Examinateur Rachel BRAS-GONÇALVES, Dr., IRD Montpellier Co-encadrant Philippe HOLZMULLER, Dr., CIRAD Montpellier Co-encadrant Amel GARNAOUI, Dr., Institut Pasteur Tunis Co-encadrant Stéphane DELBECQ, Pr., Faculté de Pharmacie Montpellier Invité Jean-Loup LEMESRE, Dr., IRD Montpellier Directeur de thèse ACKNOWLEDGEMENTS Undertaking this PhD has been a eventful and exciting experience and it would not have been possible without the support and guidance that I received. This project has received funding from the European Union 's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie International Training Network grant agreemen t No 642609. I gratefully acknowledge the additional funding received towards my PhD from Fondation des Treilles and SATT AxLR. I would like to express my sincere gratitude to my supervisor Dr. Jean-Loup Lemesre for his guidance and help throughout my PhD. I am grateful for his continuous support, encouragement and optimism which have made my PhD experience productive and stimulating. I would like to thank the thesis committee and all the PhD defense jury members. A special thanks to Dr. Rachel Bras-Gonçalves and Dr Phillippe Holzmuller for their insightful comments and expertise, but also for the fruitful discussions and their contribution to this work. I would like to thank Dr. Amel Garnaoui for the scientific collaboration, her support and assistance of my thesis work during my stays in Tunis. My sincere thanks also goes to Dr. Bernard Maillere who provided me an opportunity to visit the laboratory and research facilities. His precious support was invaluable for this research project and my PhD thesis. I would like to thank Dr. Etienne Loire and Dr. Vincent Bonhomme for their significant aid and support, determinant to this thesis work. My thanks also go out to the support I received from the collaborative work I undertook with the Plateforme de Protéomique Fonctionnelle de Montpellier. I would also like to thank Elodie Petitdidier and Julie Pagniez, great labmates who have helped and motivated me, and made the lab a friendly place. I am grateful to my sister, mother and father for the support they provided me my entire life. A special and heartfelt thanks to Nuno. I am also grateful to my other family members and friends who have supported me along the way. i ABSTRACT Leishmaniasis is a vector-borne neglected tropical disease endemic to 98 countries worldwide. Twenty Leishmania species are capable of establishing intracellular infection within human macrophages, causing different clinical presentations. Vaccine development against leishmaniases is supported by evidence of natural immunity against infection, mediated by a dominant cellular Th1 response and production of IFN-γ, IL -2 and TNF-α by polyfunctional TCD4+ and TCD8+ cells, ultimately leading to macrophage activation and parasite killing. Excreted-secreted proteins are important virulence factors present throughout Leishmania life stages and are able to induce durable protection in dogs, a good model for human infection. We aim to develop a second generation vaccine from the Leishmania secretome, with the potential for large scale dissemination in a cost-effective, reproducible approach. The secretome of six main pathogenic species (plus L. tarentolae ) was analysed by Mass- Spectrometry and conserved candidate antigens were searched in the complete dataset. A total of 52 vaccine antigen candidates were selected, including 28 previously described vaccine candidates, and an additional 24 new candidates discovered through a reverse vaccinology approach. In silico HLA-I and –II epitope binding prediction analysis was performed on all selected vaccine antigens, with world coverage regarding HLA restriction. To select the best epitopes, an automated R script was developed in-house, according to strict rational criteria. From thousands of potential epitopes, the automated script, in combination with optimal IC50, homology to host and solubility properties, allowed us to select 50 class I and 24 class II epitopes, synthesized as individual peptides. In vitro toxicity assays showed these selected peptides are non-toxic to cells. The peptides’ immunogenic ity was evaluated using immunoscreening assays with immune cells from human donors, allowing for the validation of in silico epitope predictions and selection, and the assessment of the peptide’s immunogenicity and prophylactic potential. Healed individuals, which had active infection and received treatment, possess Leishmania -specific memory responses and are resistant to reinfection, being considered the gold standard of protective immunity. On the other hand, the naive population is extremely important to include in the experimental validation step since it is the target population to vaccinate with a prophylactic vaccine. Importantly, a minimum specific T-cell precursor frequency is needed to induce long-lasting memory protective responses. Furthermore, there is also a positive correlation between immunodominant epitopes and a high frequency of specific T-cell precursors. Peptides able to induce Th1 and/or cytotoxic immune responses in both background are promising candidates for a vaccine formulation. Altogether, ii experimental validation exclusively in human samples will provide us a very strong base for a vaccine formulation and allow to accelerate translation to the field. Results show Leishmania -specific peptides successfully induce IFN-γ production by total PBMC from healed donors, and by specific T cells amplified from the naïve repertoire. Preliminary evidence exists for peptides which are immunogenic in both immune backgrounds (eight HLA-class I 9-mer peptides and five class II 15-mer peptides) which are, for now, the most promising candidates to advance for the multi-epitope peptide design. Through the combination of proteomic analysis and in silico tools, promising peptide candidates were swiftly identified and the secretome was further established as an optimal starting point for vaccine development. The proposed vaccine preclinical development pipeline delivered a rapid selection of immunogenic peptides, providing a powerful approach to fast-track the deployment of an effective pan-specific vaccine against leishmaniases. iii RESUMÉ La leishmaniose est une maladie tropicale négligée à transmission vectorielle qui est endémique dans 98 pays dont les plus pauvres. Vingt espèces de Leishmania sont capables d’établir une infection intracellulaire au sein des macrophages humains, provoquant différentes manifestations cliniques. Le développement d'un vaccin contre les leishmanioses est étayé par des preuves d'immunité naturelle contre l'infection, induite par une réponse à médiation cellulaire de type Th1 dominante associée à la production d'IFN-γ, d'IL -2 et de TNF-α par des cel lules T polyfonctionnelles TCD4 + et TCD8 +, conduisant à l'activation classique des macrophages entrainant la destruction des parasites. Induire une protection robuste et durable et déterminer les épitopes immunodominants responsables de la protection naturelle représente un véritable défi. Les protéines sécrétées sont des facteurs de virulence jouant un rôle important dans le cycle de vie des leishmanies et sont capables d’induire une protection durable chez le chien, un bon modèle pour l’infection humaine. Notre objectif est de développer, à partir du sécrétome de Leishmania , un vaccin de seconde génération reproductible et facile à produire à bas prix dans les zones d’endémie, avec des rendements de production rendant possible son utilisation à grande échelle. Les sécrétomes des six espèces les plus pathogènes de leishmanie (plus L. tarentolae ) ont été analysés et comparées par spectrométrie de masse. Les antigènes candidats ont été recherchés dans l'ensemble des données protéomiques disponibles. 52 antigènes candidats vaccin ont ainsi été sélectionnés, dont 28 avaient déjà été décrits dans la littérature
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