Characterization of Broadly Neutralizing Coronavirus Spike Protein Antibodies

The two global outbreaks of severe acute respiratory syndrome (SARS) and Middle-East respiratory syndrome (MERS) underscored the recurring threat of cross-species transmission of coronaviruses (CoVs) to humans. One of the major challenges in CoV drug development are high variation rates in the receptor binding domain (RBD) of the viral spike (S) protein, which is responsible for host receptor binding and membrane fusion. This leads to a wide host and tissue tropism and makes established antibodies (Abs) against the RBD of narrow breadth. Currently, no approved antivirals or vaccines are available for any specific human CoV and no broadly neutralizing antibodies or inhibitors are known against these pathogens. New vaccination strategies are therefore urgently needed to combat these zoonotic viruses and prevent future outbreaks. In this project, we will use high-resolution molecular imaging and computational protein design to isolate and characterize cross-reactive neutralizing Abs targeting conserved regions of SARS-CoV and MERS-CoV and use this information to guide the design of next-generation subunit vaccines against these viruses. We will utilize single-particle cryo-electron microscopy (cryo-EM) to characterize complexes between broadly neutralizing Abs and the S protein of MERS-CoV and SARS-CoV to elucidate the mechanisms of viral inhibition. We will subsequently leverage this structural information to guide the engineering of next-generation subunit vaccine candidates capable of focusing the immune response toward the epitopes identified by cryo-EM. The proposed project will yield the first broadly protecting CoV Abs, pave the way for the development of a universal CoV subunit vaccine and establish a framework for the generation of epitope-based therapeutics targeting other rapidly evolving zoonotic virus families. Keywords MERS; epitope-focused vaccine design; cryo-electron microscopy; viral fusion proteins; SARS; coronaviruses; broadly-neutralizing antibodies Hauptdisziplin Strukturforschung