Equipe d’Accueil : U1184 IMVA-HB/IDMIT (CEA, INSERM, UPSaclay)
Intitulé de l’Unité : Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes
(IMVA-HB)/ Infectious Diseases Models for Innovative Therapies (IDMIT)
Nom du Responsable de l’Unité : Roger LE GRAND
Nom du Responsable de l’Équipe : Roger LE GRAND
Adresse : 18, route du panorama, 92265 Fontenay-aux-Roses
Responsable de l’encadrement : Anne-Sophie BEIGNON
Tél : 0146548027…… Fax : ……………………… E-mail: a n n e – s o p h i e . b e i g n o n @ c e a . f r

Résumé du projet 
CONTEXT. HIV/AIDS pandemic remains a major public health concern: 38 million people live with HIV (PLWH) in the world today and 1.5 million become newly infected yearly. The development of innovative approaches to fight HIV infection, including prophylactic and therapeutic vaccines, remains a priority to end the HIV/AIDs pandemic. The mRNA lipid nanoparticle (LNP) platform presents a highly promising potential for HIV-1 vaccines. However, there is evidence that its immunogenicity and long term efficacy need to be reinforced, which is usually obtained through the effects of adjuvants.
PROJECT. We aim to develop and evaluate the reactogenicity and potential to induce potent SIV/HIV specific cellular and humoral immunity of a vaccine platform combining mRNA-LNP and the STING agonist cGAMP as adjuvant. STING agonists are potent inducers of type I interferon (IFN) secretion and represent promising immunomodulators promoting the induction of strong cellular and humoral responses. This is a 2-year collaborative project (2024-2025) led by Victor Appay (U1303 INSERM Immunoconcept, Bordeaux) and based on his prior work on T cell priming (Gutjahr et al., JCI Insight 2019; Cabral-Piccin et al., EBioMedicine. 2023). It involves Stéphane Paul (GIMAP, Université Saint Etienne Saint-Priest en Jarez), expert in mucosal immunity; Bernard Verrier (UMR5305 CNRS-UCBL, Lyon), expert in mRNA vaccines; Yamamoto Takuya (Osaka, Japan), expert in HIV vaccines; and Anne-Sophie Beignon (IDMIT, Fontenay-aux-Roses) expert in innate immunity induced by vaccines, including trained immunity and NHP models (Feraoun et al., Front Immunol 2022 ; Palgen et al, NPJ Vaccines 2020). The LNP vectors encapsulating mRNA encoding SIV/HIV antigens have been designed and produced already. The STING agonist is commercial. The formulations combining mRNA-LNP with or without cGAMP are being studied using complementary models of study and assays : in vitro with human cells and in vivo in mice, by the other members of the consortium. M2 PROJECT. The M2 intern will perform a complementary analysis. She or he will characterize the innate/inflammatory, IFN type I effector responses and innate memory responses induced in vitro by LNP vectors encapsulating mRNA encoding SIV gag, adjuvanted or not with cGAMP using macaque primary cells (leukocytes, PBMC, monocytes). Cytokines will be quantified by luminex, activation/maturation and cellular metabolism will be studied by mass cytometry and transcripts will be analyzed using NanoString’s nCounter or RNA-Seq. Moreover, upon adjuvanted or not mRNA-LNPs in vitro stimulation of macaque PBMCs, the M2 intern will also study vaccine Ag expression and T cell activation by comparing naïve versus SIV infected ARV treated animals. This type of studies have been recently performed at IDMIT by the group of Anne-Sophie Beignon with candidate malaria vaccines adjuvanted with RIG-I agonists with success, including the in vitro training of monocytes assay (non published yet), except the Ag-specific T cell activation assay, which will need to be developed by the M2 intern. The M2 intern will benefit from the expertise of several IDMIT core facilities, including for high-dimensional data analysis, and from an inspiring and solid scientific and technological environment at IDMIT.
This work is a preliminary step towards prophylactic and therapeutic vaccine efficacy studies in monkeys.

Dernières Publications en lien avec le projet :
1: Van Tilbeurgh M, Maisonnasse P, Palgen JL, Tolazzi M, Aldon Y, Dereuddre-Bosquet N, Cavarelli M, Beignon AS, Marcos-Lopez E, Gallouet AS, Gilson E, Ozorowski G, Ward AB, Bontjer I, McKay PF, Shattock RJ, Scarlatti G, Sanders RW, Le Grand R. Innate cell markers that predict anti-HIV neutralizing antibody titers in vaccinated macaques. Cell Rep Med. 2022 Oct 18;3(10):100751. doi: 10.1016/j.xcrm.2022.100751. Epub 2022 Sep 26. PMID: 36167072; PMCID: PMC9588994.
2: Feraoun Y, Palgen JL, Joly C, Tchitchek N, Marcos-Lopez E, Dereuddre-Bosquet N, Gallouet AS, Contreras V, Lévy Y, Martinon F, Le Grand R, Beignon AS. The Route of Vaccine Administration Determines Whether Blood Neutrophils Undergo Long-Term Phenotypic Modifications. Front Immunol. 2022 Jan 4;12:784813. doi: 10.3389/fimmu.2021.784813. PMID: 35058925; PMCID: PMC8764446.

3: Palgen JL, Feraoun Y, Dzangué-Tchoupou G, Joly C, Martinon F, Le Grand R, Beignon AS. Optimize Prime/Boost Vaccine Strategies: Trained Immunity as a New Player in the Game. Front Immunol. 2021 Mar 8;12:612747. doi: 10.3389/fimmu.2021.612747. PMID: 33763063; PMCID: PMC7982481.
4: Palgen JL, Tchitchek N, Rodriguez-Pozo A, Jouhault Q, Abdelhouahab H, Dereuddre-Bosquet N, Contreras V, Martinon F, Cosma A, Lévy Y, Le Grand R, Beignon AS. Innate and secondary humoral responses are improved by increasing the time between MVA vaccine immunizations. NPJ Vaccines. 2020 Mar 19;5(1):24. doi: 10.1038/s41541- 020-0175-8. PMID: 32218996; PMCID: PMC7081268.
5: Palgen JL, Tchitchek N, Elhmouzi-Younes J, Delandre S, Namet I, Rosenbaum P, Dereuddre-Bosquet N, Martinon F, Cosma A, Lévy Y, Le Grand R, Beignon AS. Prime and Boost Vaccination Elicit a Distinct Innate Myeloid Cell Immune Response. Sci Rep. 2018 Feb 15;8(1):3087. doi: 10.1038/s41598-018-21222-2. PMID: 29449630; PMCID: PMC5814452.

Ce projet s’inscrit dans la perspective d’une thèse mais pas forcément sur la poursuite de ce projet de M2
Type de financement prévu : concours ED, concours CEA CFR
Ecole Doctorale de rattachement : ED569 (Innovation thérapeutique : du fondamental à l’appliqué),