Description

The most severe forms of malaria are caused by the parasite Plasmodium falciparum, whose virulence is associated with infected erythrocytes (IEs) sequestration from blood circulation by binding to endothelial cells surface receptors within microvessels of various tissues (1). Adhesion of IEs is mediated by members of the highly polymorphic and clonally variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) exported to the IEs surface. Whereas the intracellular acidic terminal segment (ATS) of PfEMP1 is conserved, the extracellular region displays an N-terminal segment (NTS) followed by various numbers of highly polymorphic Duffy-binding-like (DBL) domains and cysteine-rich inter-domain region (CIDR), also termed ID. Specific antibodies to PfEMP1 are crucial in clinical immunity acquired by people living in malaria endemic areas. Placental malaria (PM) is the best proof of concept that clinical immunity is correlated to neutralizing antibodies targeting a specific PfEMP1 (2). PM is characterized by the massive accumulation of IEs and monocytes in the placental intervillous blood spaces, and causes adverse birth outcomes, notably low birth weight and increased perinatal and maternal mortality. Chondroitin sulfate A (CSA) is the primary receptor for IEs sequestration in the placenta and VAR2CSA is the PfEMP1 family member responsible for IEs cytoadhesion to CSA. Antibodies targeting VAR2CSA and inhibiting the interaction with CSA have been correlated with PM protection. Therefore, VAR2CSA stands today as the leading vaccine candidate that could serve to protect pregnant women against PM (3).
We have recently reported the safety and immunogenicity of a VAR2CSA-derived PM vaccine (PRIMVAC) spanning the CSA-binding DBL1x-2x of the 3D7-VAR2CSA variant in malaria naïve and P. falciparum-exposed non-pregnant women in a Phase Ia/Ib clinical trial (ClinicalTrials.gov, NCT02658253). Although the vaccine was shown to be safe and induce antibodies reacting and inhibiting CSA-binding of the homologous strain, limited cross-reactivity with other VAR2CSA variants was observed. (4)
The Severe malaria pathogenesis team is working on the development of vaccine and Immunotherapies approaches aiming to protect against placental malaria.
We are aiming to develop an experimental mRNA-based placental malaria vaccine candidate able to generate high levels of antibodies reacting against various VAR2CSA variants and able to inhibit the adhesion of infected erythrocytes to CSA.
The PhD student will participate in the design and the characterization of the humoral immune response developed in rats/mice vaccinated with different Placental malaria mRNA vaccines candidates in combination with different LNPs. The best mRNA vaccine candidate will also be combined with other mRNA vaccines notably mRNA vaccines targeting the blood stage and/or the preerythrocytic stage of the parasite.
The PhD will then have to employ different molecular biology, Biochemistry and various Immunology technics to assess the generated humoral immune response of the vaccinated animals.

Compétences requises

Formation académique : • Diplôme requis : Master 2 (ou équivalent) en immunologie, biologie moléculaire, microbiologie, virologie, ou biotechnologie, avec une spécialisation ou une expérience en vaccinologie, parasitologie ou biologie des pathogènes. • Atouts supplémentaires : Expérience en recherche translationnelle, en développement de vaccins, ou en thérapies à base d’ARN. Compétences techniques souhaitables : • Biologie moléculaire : Maîtrise des techniques de clonage, PCR, RT-qPCR, séquençage, et manipulation de vecteurs d’expression (ex. : plasmides, ARN). • Biochimie : Expérience en purification de protéines, Western blot, ELISA, et techniques de caractérisation des anticorps (ex. : titration, tests de neutralisation). • Immunologie : Connaissance des techniques d’évaluation de la réponse immunitaire humorale (ex. : dosage d’anticorps, tests de liaison et d’inhibition, cytométrie en flux). • Modèles animaux : Expérience avec des modèles murins ou de rongeurs (souris/rats) pour des études vaccinales, incluant l’immunisation, le prélèvement d’échantillons, et l’analyse des réponses immunitaires.

Bibliographie

1. World Health Organization, Geneva. World Malaria Report 2019 (2019). ISBN 978-92-4-156572-1. Licence: CC BY-NC-SA 3.0 IGO.

2. Tomlinson, A.; Semblat, J. P.; Gamain, B.; Chene, A., VAR2CSA-Mediated Host Defense Evasion of Plasmodium falciparum Infected Erythrocytes in Placental Malaria. Front Immunol 2020, 11, 624126.http://dx.doi.org/10.3389/fimmu.2020.624126

3. Gamain, B.; Chene, A.; Viebig, N. K.; Tuikue Ndam, N.; Nielsen, M. A., Progress and Insights Toward an Effective Placental Malaria Vaccine. Front Immunol 2021, 12, 634508.http://dx.doi.org/10.3389/fimmu.2021.634508

4. Sirima, S. B.; Richert, L.; Chene, A.; Konate, A. T.; Campion, C.; Dechavanne, S.; Semblat, J. P.; Benhamouda, N.; Bahuaud, M.; Loulergue, P.; Ouedraogo, A.; Nebie, I.; Kabore, M.; Kargougou, D.; Barry, A.; Ouattara, S. M.; Boilet, V.; Allais, F.; Roguet, G.; Havelange, N.; Lopez-Perez, E.; Kuppers, A.; Konate, E.; Roussillon, C.; Kante, M.; Belarbi, L.; Diarra, A.; Henry, N.; Soulama, I.; Ouedraogo, A.; Esperou, H.; Leroy, O.; Batteux, F.; Tartour, E.; Viebig, N. K.; Thiebaut, R.; Launay, O.; Gamain, B., PRIMVAC vaccine adjuvanted with Alhydrogel or GLA-SE to prevent placental malaria: a first-in-human, randomised, double-blind, placebo-controlled study. Lancet Infect Dis 2020, 20 (5), 585-597.http://dx.doi.org/10.1016/S1473-3099(19)30739-X

Mots clés

Paludisme, placenta, grossesse, vaccin