Betacoronaviruses can cause deadly, rapidly spreading zoonotic infections. The world is currently witnessing the global spread of COVID-19, which is caused by SARS-CoV-2 and has killed already almost 3000 people. There are no vaccines or antivirals on the market to prevent or treat disease caused by these newly emerging beta coronaviruses. The aim of this project is to develop an antibody-based biological that can neutralize a broad range of beta coronaviruses, including SARS-CoV, MERS-CoV and SARS-CoV-2. To reach this goal we will first select potently neutralizing single domain antibodies that are directed against the receptor-binding domain of the beta coronavirus spike proteins. These single domain antibodies, which are expected to have a limited breadth, will be genetically fused with broadly neutralizing single domain antibodies that are directed against the more conserved S2 domain of the beta coronavirus spike proteins. Importantly, we will develop a novel functional selection strategy to identify the most broadly and potently neutralizing single domain antibodies from a very rich beta coronavirus spike protein-directed single domain cDNA library. The resulting heterobivalent antibody constructs will in turn be fused with a conventional IgG Fc domain and assessed in vitro and in vivo for their neutralizing and protective potency against a broad set of beta coronaviruses, including SARS-CoV, MERS-CoV and SARS-CoV-2.