Speaker
Description
Selection pressures on SARS-CoV-2 molecular phenotypes have changed dramatically in time since the virus’s emergence. Initially, for example, the greatest pressure was on enhancing the virus's intrinsic biological traits in order to increase its transmissibility in the naive population. Then, as population immunity grew from previous infections and vaccination, immunity became the primary factor limiting further spread and hence more pressure was put on escaping it. This transition has been inferred largely from the changing phenotypic properties of the virus. However, the actual changes in the underlying virus fitness landscape, which must have facilitated this transition and others, remain little understood.
In this work we present a comprehensive analysis of both the time-changing selection pressures on different molecular phenotypes, and the corresponding gradients in the fitness landscape. Our method integrates both deep mutational scanning data on the phenotypic effect of mutations on in-vitro phenotypes, and a state-of-the-art phylogenetic fitness method to estimate the fitness effect of mutations.
We demonstrate that an increase in the gradient of the fitness landscape against a particular phenotype often results in changes in evolutionary pressures on the virus population (as described by the classical Price equation) and therefore in shifts in the population value of that phenotype. These changes in the fitness landscape are therefore meaningful, and reveal the history of evolutionary pressures acting on the virus.
We observe waves of immune escape against specific monoclonal antibodies, and particular RBD epitopes more broadly. Epitopes involved in selection pressure for immune escape changed dramatically for more recent variants starting with JN.1. Furthermore, we show that while immune escape became an important driver with the emergence of Omicron, selection pressure on ACE2 binding has never diminished and remains an important evolutionary pressure to the present day.
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