Enveloped viruses use membrane fusion proteins to deliver their genome into the host cell. Many human viruses use so-called class 1 fusion proteins to mediate this virus entry step. The formation of a six-helix bundle by zippering up of the carboxy-terminal heptad repeat (HR) with the amino terminal HR is a hallmark of class 1 fusion proteins that is essential for membrane fusion. Our aim is to generate vaccines and antibody-based antiviral drug candidates that can prevent the six-helix bundle formation by tightly locking the carboxy-terminal HR in its trimeric prefusion state. We will apply a structure-guided design of immunogens that focus the immune response to the trimeric carboxy-terminal HR as it is present in the prefusion conformation of the viral class 1 fusion protein. Antibody-based candidate biologics that selectively bind with high affinity to the trimeric carboxyterminal HR in the prefusion state will be selected from natural as well as synthetic single-domain antibody display libraries. We will also evaluate the possibilities of de novo designed single-domain antibody approaches, a rapidly evolving field in computational biology. Our approach will be applied to the fusion proteins of corona-, Nipah- Hendra-, and Ebola viruses. This project is inspired by our recent discovery of ultra-potent SARS-CoV-1- and -2-neutralising single-domain antibodies that specifically bind the trimeric, carboxy-terminal HR of the spike protein.