Deconstructing the protective immunity of yellow fever virus 17D to inform flavivirus vaccine design

While endemic to the tropics, flaviviruses like Zika, dengue, West Nile or yellow fever virus are re-emerging pathogens of global health concern. Climate change and urbanization have largely contributed to the dissemination of their mosquito vector and Europe has in recent years been regularly confronted with autochthonous cases. Few vaccines are licensed to prevent flavivirus disease, but the yellow fever 17D (YF17D) vaccine has a unique track record of efficiency and safety. Intriguingly, despite its success, how YF17D induces immunity remains poorly understood. The YELLOW4FLAVI consortium aims to fill the gaps in our understanding of the mechanism of action of this vaccine by linking the structure of the viral particle to the resulting host immune response, in order to learn about optimal vaccine design for flaviviruses in general. Since social acceptance of vaccines is critical for their success, we will also develop optimal communication methods. This will provide us with the tools to tailor vaccine design not only to achieve optimal immune protection, but also to facilitate actual implementation.We are molecular and structural virologists, cell biologists, immunologists, computational scientists, clinicians, and social scientists assembled in a tight collaborative network. To pursue our goal of obtaining a blueprint for determinants of long-lasting immunity for flavivirus vaccine candidates, we will use cutting-edge technologies like cryo-EM, super resolution microscopy, spatial transcriptomics, high-dimensional spectral flow cytometry, single-cell RNA sequencing, advanced cell engineering, small animal models, and clinical studies. In a unique manner, the consortium thereby follows a thread of events from the early response at the site of vaccine injection to the population perception of vaccination, harnessing an enhanced understanding of one of the most successful vaccines of mankind for the development of novel lines of defense against new and old threats.