Title: Combatting a continuously evolving pathogen, SARS-CoV-2
Description: The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic has led to widespread socioeconomic and clinical damage. The coalescent response from the global scientific community has been unparalleled, both in speed and furor. Numerous efficacious interventions have been developed and deployed, including several vaccines, antibody therapies, and drugs. Yet, SARS-CoV-2 embodies the quintessential virological issue which threaten these achievements; rapid evolution in the face of selective pressure. This dissertation investigates such adaptations by SARS-CoV-2, and accordingly, modalities to combat this virus despite such evasive measures. To this end, we first studied the antigenic properties of several members of the B.1.1.529 or Omicron lineage of SARS-CoV-2. We observed that B.1.1.529.1 (BA.1), B.1.1.529.1.1 (BA.1.1), and B.1.1.529.2 (BA.2) are the most antibody resistant SARS-CoV-2 variants to-date, while being antigenically unique between each other. Consequently, we turned to explore modalities which may withstand such formidable resistance.

We undertook some of the first explorations of a heterologous booster vaccination regimen, finding expanded breadth and potency against SARS-CoV-2, suggesting it may be one simple measure that could be utilized. We also sought to identify broadly neutralizing SARS-CoV-2 antibodies, isolating several with breadth against coronaviruses beyond that of SARS-CoV-2. One of these antibodies, 10-40, was determined to be the broadest receptor-binding domain-directed antibody reported to-date. Finally, we examined an alternative viral target, the 3CL protease. We discovered several SARS-CoV 3CL protease inhibitors that could be repurposed for inhibition of SARS-CoV-2 and determined their crystal structures, which could allow for their use as lead compounds. We further developed and conducted a deep mutational scan of the 3CL protease to examine the activity of all possible single point mutants, revealing that the enzyme had unexpected malleability, as well as several conserved sites that may be targeted by future inhibitors.

The SARS-CoV-2 pandemic has been a remarkable trial, but has also served to demonstrate the good that science can do. We hope that this work has been a small contribution among such difficult times.