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 adverse effects of pharmaceuticals on the central or peripheral nervous systems are poorly predicted by the current in vitro and in vivo preclinical studies performed during Research and Development (R&D) process. Therefore, increasing the predictivity of the preclinical toolbox is a clear need, and would benefit to human volunteers/patients (safer drugs) and Pharmaceutical Industry (reduced attrition). By combining top level scientists in neurobiology/toxicology with successful software developers, the NeuroDeRisk | Neurotoxicity De-Risking in Preclinical Drug Discovery Consortium will aim at tackling three of the most challenging adverse effects: seizures, psychological/psychiatric changes, and peripheral neuropathies. Our approach will be global, starting with an in-depth evaluation of knowledge on mechanisms of neurotoxicity (biological pathways as well as chemical structures and descriptors, using in particular historical data). Then we will search for innovative tools, assays and studies covering in silico, in vitro and in vivo approaches. This will include in particular: molecular design platform, artificial intelligence, human induced pluripotent stem cells, blood-brain-barrier models, immunohistochemistry, transcriptomics, RNA editing biomarkers, video-monitoring and telemetry of animals, pharmacokinetics, etc. The last step will aim at combining these tools in an integrated platform for better risk-assessment and decision-points throughout R&D process, and thus better protection of human volunteers and patients.

Today’s major challenge is to improve efficacy of vaccines to protect the growing ageing population against infectious diseases (ID). The VITAL project aims to address this challenge by assessing the ID burden and mechanisms of immunosenescence to provide evidence-based knowledge on vaccination strategies to establish healthy ageing. Links with existing projects containing data sources combined with novel data acquired through our extensive network of dataregistries across Europe will result in a database of epidemiology, risk factors and burden of disease of both vaccine-preventable (VP) and potential vaccine-preventable ID. Crucial knowledge on factors that hamper immune responsiveness and in-depth analyses of immune compartments involved in inducing effective immune responses to different vaccines in the ageing host will be gathered. We will identify novel predictive, potentially universal immune profiles of vaccine responses using novel technologies, unique experimental models and (infection) cohorts of elderly subjects in which (bio)markers of frailty have already been identified. Novel strategies to address the problem of immunosenescence will be tested, in particular whether vaccination of middle-aged individuals can maintain proper memory immune responses in the elderly, to improve memory immunity before reaching old age. Using data on epidemiology of VPID and immune responsiveness, novel agent-based models will be developed to build a user-friendly tool to be used by health care professionals for optimal implementation of vaccination strategies for older people and to develop dissemination protocols for the obtained knowledge for the health care field. Finally, we will deliver a framework that forms the basis for designing, implementing and regularly updating vaccination schemes for the ageing population. Thereby, VITAL will initiate an important impetus to a more targeted immunization program for the elderly in Europe that will enhance healthy aging.