Neutralizing and cross-reactive monoclonal antibodies against SARS-CoV-2 and other betacoronaviruses

After virus infection, or upon vaccination our immune system develops a repertoire of functionally diverse antibodies against the viral proteins. Only a limited part of these antibodies provides protection. This thesis describes the quest for antibodies that protect against coronavirus infection, and particularly of those that can broadly inhibit infection of multiple, related coronaviruses. The spike protein of coronaviruses is the main target of neutralizing antibodies that prevent infection of the host cell. In our studies, we describe the isolation of antibodies directed against the spike proteins of several human-infecting (beta)coronaviruses including the MERS coronavirus, the SARS coronavirus, and the SARS coronavirus 2 that causes the COVID-19 pandemic. Evaluation of these antibodies allowed us to uncover several vulnerable sites on the spike proteins of various coronaviruses. Some of these antibodies exhibit a remarkable broad reactivity and inhibit infection of several related coronaviruses. We show that the broad reactivity of these antibodies is due to binding to sites on the spike protein that have been well conserved during the evolution of these viruses from a common ancestor. The identification and analysis of such antibodies and their binding sites on the spike protein can help us to develop antibody therapeutics and/or vaccines that can provide broad immunity against virus variants or newly emerging coronaviruses.