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Thesis Reference Thesis L'épidémie de la maladie du virus Ebola et le vaccin VSV-EBOV : un essai clinique de phase I dans une situation d'urgence CSAKI HUTTNER, Angela Abstract L'épidémie actuelle de maladie du virus Ebola a été reconnue en Guinée en Mars 2014. La maladie a touché plus que 10 pays sur trois continents, et aux Etats Unis et en Espagne, des transmissions nosocomiales ont eu lieu. La portée de l'épidémie a déclenchée un certain degré de panique et, enfin, une collaboration internationale sans précédent. En automne 2014, sous la coordination de l'Organisation mondiale de la santé, les Hôpitaux universitaires de Genève ont lancé un essai de phase I pour tester la sécurité et immunogénicité du candidat vaccin le plus prometteur. Cette étude randomisée, contrôlée par placebo a inclus 115 volontaires sains. Le vaccin a été réactogène mais fortement immunogène ; résultats inattendus comprenaient des arthrites, dermatites, et vasculites cutanées liées au vaccin. Ces effets secondaires ont été enfin auto-limités, et le vaccin a été sélectionné pour des essais ultérieurs (phase III) sur le terrain. Reference CSAKI HUTTNER, Angela. L'épidémie de la maladie du virus Ebola et le vaccin VSV-EBOV : un essai clinique de phase I dans une situation d'urgence. Thèse de doctorat : Univ. Genève, 2016, no. Méd. 10827 DOI : 10.13097/archive-ouverte/unige:94945 URN : urn:nbn:ch:unige-949452 Available at: http://archive-ouverte.unige.ch/unige:94945 Disclaimer: layout of this document may differ from the published version. 1 / 1 Section de médecine Clinique Département des spécialités de médecine Service des maladies infectieuses Thèse préparée sous la direction du Professeur Laurent KAISER " L'épidémie de la maladie du virus Ebola et le vaccin VSV-EBOV : un essai clinique de phase I dans une situation d’urgence " Thèse présentée à la Faculté de Médecine de l'Université de Genève pour obtenir le grade de Docteur en médecine par Dre Angela HUTTNER de New York, New York, Etats Unis Thèse n° 10827 Genève, Suisse 12 octobre 2016 THESE EN MEDECINE – DRE ANGELA HUTTNER My dear Gorgas, instead of being simply satisfied to make friends and draw your pay, it is worth doing your duty, to the best of your ability, for duty’s sake; and in doing this, while the indolent sleep, you may accomplish something that will be of real value to humanity. Your good friend, Reed. Dr. Walter Reed to Dr. William Gorgas, 18981 2 THESE EN MEDECINE – DRE ANGELA HUTTNER Table of Contents Résumé (français) ................................................................................................................................. 5 1 Prelude to a phase I, first-in-human clinical trial: the Ebola virus and the 2013 – 2016 epidemic ...... 16 1.1. The Ebola virus ......................................................................................................................... 16 1.2 Ebola virus disease .................................................................................................................... 16 1.3 Transmission of Ebola virus ....................................................................................................... 18 1.4 The 2013 – 2016 Ebola virus epidemic ....................................................................................... 19 1.5 Prevention of Ebola virus transmission: still in the Dark Ages .................................................... 20 2 The need for an effective Ebola vaccine ............................................................................................ 21 2.1 State of the art: Ebola vaccine development through 2014 ........................................................ 21 3 The VSV-EBOV vaccine ..................................................................................................................... 22 3.1 History of the VSV-EBOV vaccine, including its journey to Geneva ............................................. 23 3.2 Overview of the vector: the vesicular stomatitis virus ............................................................... 23 3.3 The rationale for moving VSV-EBOV into clinical trials ............................................................... 24 Lack oF reassortment & cytosolic replication ..................................................................................... 24 High expression oF EBOV-GP .............................................................................................................. 25 ModiFication oF soluble EBOV-GP ...................................................................................................... 25 Clinical data in humans beFore phase I testing .................................................................................. 27 4 The Geneva VSV-EBOV phase I trial: preparation and launch ............................................................ 28 4.1 The VEBCON Consortium ........................................................................................................... 28 4.2 Geneva trial preparation, design & launch ................................................................................. 29 Study objectives ................................................................................................................................. 29 Trial design ......................................................................................................................................... 30 Determination oF sample siZe ............................................................................................................ 31 Entry criteria ...................................................................................................................................... 32 Run-in phase ...................................................................................................................................... 32 Selection oF doses .............................................................................................................................. 32 Selection and timing oF dose .............................................................................................................. 33 Blinding .............................................................................................................................................. 33 3 THESE EN MEDECINE – DRE ANGELA HUTTNER 5 Trial findings .................................................................................................................................... 33 5.1 Safety findings ........................................................................................................................... 34 5.2 Immunogenicity results ............................................................................................................. 36 6 The end of a trial – and the beginning of everything ......................................................................... 36 Final note ........................................................................................................................................... 37 4 THESE EN MEDECINE – DRE ANGELA HUTTNER Résumé (français) Introduction Contexte L'épidémie actuelle de maladie du virus Ebola a été reconnue en Guinée en Mars 2014, mais a commencé dans ce pays en Décembre 2013. A ce jour, l'épidémie a causé 28,646 cas (conFirmés, probables et suspects) et 11,323 décès. Le taux de mortalité est estimé autour de 50%. Cependant, ces chiFFres sous-représentent probablement largement l'ampleur réelle de l'épidémie, et dans certaines régions la mortalité était supérieure 70%. La maladie a touché principalement trois pays en Afrique de l’ouest, à savoir la Guinée, la Sierra Leone et le Libéria. Quelques cas ont également été recensés au Mali, au Nigeria et au Sénégal, et des patients inFectés en AFrique de l’ouest, majoritairement des soignants occidentaux, ont été rapatriés et soignés au Royaume-Uni, en Allemagne, en France, en Norvège, en Suisse, en Espagne et aux États-Unis. Dans ces deux derniers pays, une transmission nosocomiale a eu lieu. L'épidémie actuelle est la première à se produire en Afrique de l'Ouest, où systèmes de soins de santé et les économies locales étaient mal équipés pour Faire Face à sa portée. Comme la propagation de l'épidémie, les hôpitaux se sont retrouvés dépassés et ont fermé, laissant d'autres besoins médicaux non traités. Il en a donc résulté un « nombre de morts supplémentaires» diFFicile à quantiFier, ayant probablement dépassé celui de l'épidémie elle-même. En dépit des avertissements au début de 2014 par des organisations médicales internationales, essentiellement Médecins Sans Frontières (MSF), l'épidémie a continué de progresser. Le 8 août 2014, l'Organisation mondiale de la santé (OMS) a répondu et a déclaré que l'épidémie relève d’une «urgence de portée internationale de la santé publique.» Dans le même mois, alors que l’ampleur de l'épidémie Ebola devenait de plus en plus hors de contrôle, l’agence de santé publique canadienne (Public Health Agency of Canada, PHAC) a Fait don de 800 Fioles d’un vaccin expérimental à l’OMS. En quelques semaines, l'OMS a contacté le ProFesseur Laurent Kaiser, médecin cheF du service des maladies inFectieuses aux hôpitaux universitaires de Genève (HUG), et a demandé le lancement d'un premier essai clinique de phase I chez l’humaine pour tester la sécurité et immunogénicité de ce candidat vaccin. 5 THESE EN MEDECINE – DRE ANGELA HUTTNER Le virus Ebola Le virus Ebola (EBOV), anciennement désigné le virus Ebola Zaïre, est l’une des cinq espèces connues appartenant au
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