Le vaccin antivariolique historique Lister : séquence génomique, diversité phénotypique et neuropathogénicité : perspectives vaccinales

The smallpox constituted a real scourge for humanity until 1980, the year of the declaration of its eradication due to vaccination. The risk of variola virus reemerging as a biological weapon, considering manufacturing conditions, the low population immunity and historical vaccine post-vaccinal complications, make new smallpox vaccines development a necessity.In this paper, the historical Lister strain vaccine study is described as part of the elaboration strategy of a new vaccine coming from this strain.The genomic sequence of this vaccine is determined and described. Its comparison with other vaccinia virus strains underlines the Lister strain singularities.The viral population diversity study as well as the phenotypic and genetic characterization should highlight strategy choice for the development of a new second generation vaccine coming from the Lister strain : a clonal vaccine or a polyclonal one.Finally, the study of the vaccinia virus interaction with the blood-brain barrier demonstrates an increase in permeability due to vaccinia virus endothelial cells infection. Moreover, in vivo studies exhibit the viral entry and replication in the brain, sometimes responsible for critical cerebral reaches. These results suggest the first generation smallpox vaccine neuropathogenesis could have caused deadly post-vaccinal encephalitises, smallpox vaccination complications.Jusqu'en 1980, date à laquelle la variole a été déclarée éradiquée suite à la pratique de la vaccination, elle a constitué un véritable fléau pour l'humanité. Le risque de réémergence du virus de la variole dans un contexte bioterroriste, compte-tenu des conditions de production, de la faible immunité de la population et des complications post-vaccinales liées aux vaccins historiques, rend le développement de nouveaux vaccins antivarioliques nécessaire.L'objectif du travail de thèse présenté dans ce mémoire est l'étude du vaccin antivariolique historique Lister dans un cadre de stratégie d'élaboration d'un nouveau vaccin issu de cette souche.La séquence génomique de ce vaccin est déterminée et décrite. Sa comparaison avec d'autres souches de virus de la vaccine met en évidence les singularités de la souche Lister. Par ailleurs, l'étude de la diversité de la population virale et sa caractérisation phénotypique et génétique devraient permettre d'éclairer le choix de la stratégie pour développer un nouveau vaccin dit de deuxième génération issu de cette souche : vaccin constitué d'un seul clone viral ou vaccin polyclonal.Enfin, l'étude de l'interaction du virus de la vaccine avec la barrière hémato-encéphalique montre une augmentation de sa perméabilité suite à l'infection des cellules endothéliales par le virus de la vaccine. De plus, des études in vivo mettent en évidence l'entrée et la réplication du virus dans le tissu cérébral, entraînant des atteintes cérébrales parfois mortelles. Ces perspectives permettent d'appréhender la neuropathogénicité du vaccin historique reliée aux encéphalites post-vaccinales, complications létales de la vaccination antivariolique

Diversité phénotypique de la population virale du vaccin antivariolique de première génération Aventis-Pasteur

GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Role of different solvents on the purification of as-synthesized nano-Ce1-xGdxO2-d powders

Ceria and rare earth-doped ceria powders have important applications in catalysis, gas sensoring, and electronics. Even if many authors report different methods for the synthesis of nano-sized doped-ceria only few of them give information about the necessary washing processes for the powder purification. The organics adsorbed on the as-synthesized particles surface strongly affect, in fact, the properties of the powder. In this work, CeO2 and Ce1-xGdxO2-d (x = 0.10, 0.20, 0.30) solid solutions were produced by polyol microwave assisted method. The amount of synthesis residues adsorbed on the as-synthesized powders was firstly evaluated. The purification ability of different solvents on the as-synthesized Ce0.80Gd0.20O1.90 was, then, accurately studied in order to obtain a clean powder without the need of any thermal treatments. The study shows that water purification allows to reduce the amount of the residues of synthesis leading to the production of nano-particles with a mono-dispersed distribution of dimensions

In vitro blood brain barrier models as a screening tool for colloidal drug delivery systems and other nanosystems

The brain is one of the least accessible organs of the body due to the presence of the blood-brain barrier (BBB), thus making drug delivery to the brain quite a challenge. Various strategies have been explored to circumvent this physiological barrier, including the use of colloidal carriers. These carriers hold great promise as they may increase the delivery of drugs into the brain by protecting them from degradation and prolonging their circulation in the blood, as well as promoting their transport through the BBB. Moreover, functionalisation of these carriers with various ligands allows specific targeting of the central nervous system compartment. Additionally, various in vitro BBB models have been developed and are increasingly useful for screening of drug delivery systems, especially cell-based models that provide mechanistic information. In fact, this paper specifically reviews selected in vitro BBB models as a screening tool for drug delivery colloidal systems

Phenotypic and genetic diversity of the traditional Lister smallpox vaccine.

International audienceAs an initial step in the development of a second-generation smallpox vaccine derived from the Lister strain, to be prepared for a variola virus threat, diversity of the traditional vaccine was examined by characterizing a series of ten viral clones. In vitro and in vivo phenotypic studies showed that the biological behavior of the clones diverged from each other and in most cases diverged from the vaccinia virus (VACV) Lister parental population. Taken together, these results demonstrate the heterogeneity of the viral population within the smallpox vaccine and highlight the difficulty in choosing one clone which would meet the current requirements for a safe and effective vaccine candidate

The Anti-Hiv Candidate Abx464 Dampens Intestinal Inflammation by Triggering Il-22 Production in Activated Macrophages

International audienceThe progression of human immunodeficiency virus (HIV) is associated with mucosal damage in the gastrointestinal (GI) tract. This damage enables bacterial translocation from the gut and leads to subsequent inflammation. Dextran sulfate sodium (DSS-exposure) is an established animal model for experimental colitis that was recently shown to recapitulate the link between GI-tract damage and pathogenic features of SIV infection. The current study tested the protective properties of ABX464, a first-in-class anti-HIV drug candidate currently in phase II clinical trials. ABX464 treatment strongly attenuated DSS-induced colitis in mice and produced a long-term protection against prolonged DSS-exposure after drug cessation. Consistently, ABX464 reduced the colonic production of the inflammatory cytokines IL-6 and TNFα as well as that of the chemoattractant MCP-1. However, RNA profiling analysis revealed the capacity of ABX464 to induce the expression of IL-22, a cytokine involved in colitis tissue repair, both in DSS-treated mice and in LPS-stimulated bone marrow-derived macrophages. Importantly, anti-IL-22 antibodies significantly reduced the protective effect of ABX464 on colitis in DSS-treated mice. Because reduced IL-22 production in the gut mucosa is an established factor of HIV and DSS-induced immunopathogenesis, our data suggest that the anti-inflammatory properties of ABX464 warrant exploration in both HIV and inflammatory ulcerative colitis (UC) disease