SHIELD

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. Yellow4FLAVI 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.

Evolvable and Rapidly Adaptable Monobodies: a broad-spectrum antiviral platform

EvaMobs is developing a rapid, flexible antiviral platform using evolvable monobodies (Mobs), small, human-derived proteins engineered to bind and inactivate viruses. Mobs are smaller than monoclonal antibodies, allowing for lower dosages, and, being derived from a human protein, are less likely to trigger an immune response. By combining computational design, pre-clinical and clinical validation, EvaMobs aims to rapidly identify potent antivirals. The platform will first target Influenza A, SARS-CoV-2, RSV, and Zika virus. This adaptable technology can address a wide range of viral threats, strengthening the EU’s pandemic preparedness. The consortium comprises 11 partners from 7 EU countries + Switzerland, and the project has received ~ 9 M€ funding from the European Health and Digital Executive Agency.

IDEntification oF novel viral Entry factors aNd DevelopmEnt of antiviRal approaches

The project aims to adopt a comprehensive and integrative platform approach moving beyond virus-centric or single-gene methodologies, and applicable to a wide range of (re-) emerging viruses. Our pipeline focuses on preventing virus entry through a host bottom-up functional genetic approach in parallel to a virus top-down glycoprotein-centered approach. On the host side, we will identify novel virus entry factors, including attachment factors and proteins involved in endosomal uptake and virus genome uncoating, while on the virus side, we will use virus glycoproteins to identify novel epitopes and broadly neutralizing nanobodies that block virus attachment and membrane fusion. By combining these approaches, DEFENDER will systematically identify and characterize novel vulnerable virus-host interaction sites laying the groundwork for new antivirals and immunogens.