Structure, Function, and Broad Neutralization of Emerging SARS-CoV-2 Variant Spikes

The COVID-19 pandemic has had devastating effects on human health, economies, and society. Through international efforts, the global scientific and healthcare community has been able to develop vaccines and therapeutic antibodies at record speeds. Although these technologies have shown promise, the global and rapid emergence of SARS-CoV-2 variants poses a significant threat to their future efficacies. Circulating SARS-CoV-2 variants have demonstrated increased infectivity and resistance to antibodies and vaccines, earning them the title "Variants of Concern" or "Variants of Interest" by the WHO. More are emerging in real time, and viral evolution will continue as we move to the next phase of this crisis. A defining feature of SARS-CoV-2 variants is the presence of characteristic mutations in spike proteins. The spike protein enables SARS-CoV-2 to infect human cells, which it does by acting as a "key" which fits a receptor or "lock" on the cell. Spike mutations can increase viral infectivity by changing the spike structure to help it fit the receptor better. Because the spike plays an important role for the virus, it also represents a vulnerability. In fact, the spike is targeted by antibody therapies and is used in vaccines to "train" the immune system for recognition. These spike mutations can alter spike structure so that the immune system cannot recognize it, and antibodies cannot bind the spike. My research aims to discover how mutations are affecting variant spikes, provide a structural mechanism for any impacts on receptor binding and antibody evasion, and identify conserved vulnerabilities which allow simultaneous targeting of all variant spikes. Having a structural knowledge of variant spikes is important for updating vaccines to "re-train" immune systems for better variant recognition. Identifying common vulnerabilities enables the design of antibodies and therapies that can broadly protect against all emerging SARS-CoV-2 variants.