UBC Theses and Dissertations

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UBC Theses and Dissertations

Molecular mechanisms of SARS-CoV-2 variant spike proteins Saville, James William


SARS-CoV-2 exhibited limited widespread genetic variability over the first year of the COVID-19 pandemic. However, approximately one year after its emergence, a slew of variants would emerge, with the Alpha variant replacing the original Wuhan-Hu-1 lineage and Beta and Gamma variants emerging soon thereafter. These and subsequent variants (Epsilon, Kappa, Delta, Omicron, and XBB) are defined by numerous mutations within their spike (S) glycoprotein which is critical for viral infection via binding the human angiotensin converting enzyme (hACE2) receptor and is the sole protein immunogen in most COVID-19 vaccines (mRNA-1273 [Moderna] and BNT162 [Pfizer] for example). Therefore, mutations within the SARS-CoV-2 S protein impact both viral pathobiology and therapeutic measures to treat viral infection. We hypothesize that variant SARS-CoV-2 spike proteins exhibit enhanced receptor (hACE2) binding affinity and monoclonal and polyclonal antibody evasion. This thesis aims to characterize the Alpha, Beta, Gamma, Epsilon, Kappa, Delta, and Omicron (BA.1 and BA.2) variant S proteins for their ability to: i) enhance hACE2 binding, ii) evade monoclonal and patient-derived antibodies (elicited by either SARS-CoV-2 infection and/or vaccination), and iii) discover structural rationale that underly these changes. We find that each variant S protein exhibits distinctive characteristics - for example the Alpha S primarily exhibits enhanced hACE2 binding, while the Omicron S proteins demonstrate significant escape from antibodies and have acquired the unique ability to bind murine ACE2. The independent study of variant mutations in isolation and in combination provide insights into mutation epistasis and enable predictions into the behaviour of future SARS-CoV-2 variants of concern. Finally, we characterize a novel antibody fragment (ab6) whose epitope confers broad neutralization across variant of concern S proteins, presenting a potential variant-resistant therapeutic target.

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