The vesicular stomatitis virus (VSV)-Zaire Ebola vaccine (VSV-ZEBOV) is a recombinant vector-based vaccine in which the VSV envelope glycoprotein was replaced with the Zaire strain Ebola virus glycoprotein. Within one year of the initiation of its clinical development, the VSV-ZEBOV vaccine has demonstrated safety, immunogenicity and a remarkably high protective efficacy against Ebola Virus Disease, using a high vaccine dose (2x107 pfu) in the WHO-sponsored VSV-ZEBOV ring-vaccination trial in adults in Guinea. However, several key questions remain unanswered, including its mode of action, its correlation with protection and reactogenicity, the expected duration of protective efficacy and determinants of long-term responses, the influence of baseline immunity on vaccine “take”, and the vaccine efficacy in children - a most vulnerable population. Following the interruption of the 2014-2015 Ebola Virus Disease (EVD) outbreak, these questions, being central to the future licensing and use of VSV-ZEBOV, may not be addressed by collecting field data. The VSV-EBOPLUS project therefore proposes to use cutting-edge systems biology approaches to address these key questions, capitalizing on the unique availability of large series of extremely well defined samples from clinical vaccine studies with the VSV-ZEBOV vaccine in three different continents (Europe, Africa, US). Specifically, the overarching objective of VSV-EBOPLUS is to comprehensively decipher the immune and molecular signatures of adult and pediatric responses elicited by VSV-ZEBOV through systems biology approaches. VSV-EBOPLUS will benefit from harmonized and standardized clinical trial protocols, in almost 1’000 adults, adolescents and children. We propose: 1) to examine early (days 0 to 7) blood samples from 512 adults injected with graded doses (from 3x103 to 1x108 pfu) of VSV-ZEBOV;

The ongoing increase of the human population accompanied by growing numbers of livestock to feed this population, as well as human invasion into natural habitats of wild animals makes humans progressively vulnerable to animal pathogens. Global trade as well as climate changes can contribute to pathogen transmission, e.g. through import of infected vectors or expansion of habitats for arthropod vectors such as mosquitoes and midges. Examples for this include recent European outbreaks of the arthropod-borne Dengue, West Nile, Schmallenberg and Usutu viruses in humans, ruminants and birds. Infectious disease outbreaks in animals are often unexpected, but we should be prepared for immediate identification of the causing agent and the evaluation of its pathogenic potential for animals and humans. Preparedness needs expertise in many areas. At surveillance sites early detection and identification of viruses involved in outbreaks is crucial. Screening of different animal species and humans who have been in close contact with (diseased) animals for known or yet undiscovered viruses will also help to be prepared for future outbreaks. Novel viruses in these populations will have to be evaluated for their pathogenicity in susceptibility studies. The HONOURs network will generate new health and scientific knowledge with the aim to locate, identify, characterize, contain, and control infections that are caused by zoonotic agents. The aim of HONOURs is to provide top-quality cross-disciplinary and supra-sectorial training to 15 promising young researchers at the interface of veterinary and human health, virology, biostatistics, and pathogen discovery. These early stage researchers will become “preparedness- experts”.