SARS Coronavirus 2 Phenotypic Evolution

SARS-CoV-2 emerged in Wuhan in December 2019 and is the causative agent of the COVID-19 pandemic. SARS-CoV-2 remains a global public health burden, causing thousands of new infections and hundreds of deaths weekly. The frequent emergence of new variants necessitates regular vaccine updates and rapid phenotypic assays to study viral evolution.

First entry mechanisms of SARS-CoV-2 were investigated, highlighting the crucial role of the multibasic cleavage site in the Spike protein for entry into human airway organoids. The serine protease TMPRSS2 facilitated this entry. Notably, for Omicron variants, the role of serine proteases in entering human airway organoids remained conserved, although the specific use of TMPRSS2 was unclear. Secondly, antigenic evolution of SARS-CoV-2 variants was studied using antigenic cartography, a multidimensional scaling technique that maps variants in antigenic space, visualizing their relationships. Omicron variants clustered separately from pre-Omicron variants and showed dispersed positioning within their cluster, indicating larger antigenic variability. Newer variants exhibited increased antigenic distance from the ancestral strain. Antigenic cartography could aid in selecting cross-reactive vaccine strains. Finally, antigenic evolution was combined with replicative fitness evolution, showing that increased replication in human airway organoids evolved concomitantly with increased antigenicity. Additionally, novel variants occasionally tolerated dips in replicative fitness, such as when a larger antigenic jump occurred.

Integrating the tools described in this thesis with full genome sequencing may allow future research to predict the phenotype of emerging variants from the genome alone. However, this will require appropriate, standardized cell systems and data interpretation methods.