Properties of coronavirus spike proteins and the antibody responses against them

Abstract

Coronaviruses have a propensity to spillover from zoonotic reservoirs and cause significant morbidity and mortality in the human population. Three coronaviruses emerged and caused significant human outbreaks in recent history: severe acute respiratory syndrome coronavirus (SARS-CoV-1) in 2003, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019. The coronavirus spike protein facilitates viral entry into target cells by engaging the host receptors and fusing the viral and host membrane together. As the primary determinant of viral entry into target cells, the coronavirus spike protein is the target of most vaccines and therapeutics. Antibodies induced by prior infection and vaccination and therapeutics may select for spike protein mutations that evade these antibodies without disrupting the spike protein’s ability to engage the host receptor and mediate membrane fusion. In the following dissertation, I detail a unique mechanism of antibody evasion induced by a mutation in the receptor binding domain of the SARS-CoV-2 spike protein. I additionally describe the impact of spike protein mutations observed in the SARS-CoV-2 Omicron variants on receptor engagement, fusogenicity, and evasion from infection- and vaccine-elicited antibodies. I further examine how updated SARS-CoV-2 vaccine formulations shape the humoral immune response. Finally, I detail the contribution of spike protein domains and epitopes to the neutralizing activity of convalescent plasma collected from individuals infected with MERS-CoV. Collectively, my work is informing the development of the next generation of coronavirus vaccines and therapeutics.