Competitive fitness of emerging SARS-CoV-2 variants is linked to their Distinctiveness relative to preceding lineages from that region

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The COVID-19 pandemic has seen the persistent emergence of fitter Variants of Concern (VOCs) that have successfully out-competed circulating strains, but the determinants of viral fitness remain unknown. Here we define Distinctiveness of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. From the perspective of viral evolution, Distinctiveness captures regional herd exposure and has the advantage over the canonical concept of mutation, which relies foremost on the reference ancestral sequence that is invariant over time. By assessing the correlation between Distinctiveness and change in prevalence for all circulating lineages in each region when a new lineage is introduced, we find that the relative Distinctiveness of emergent SARS-CoV-2 lineages is associated with their competitive fitness (Pearson r = 0.67). Further, by assessing the Delta variant in India versus Brazil, we show that the same lineage can have different Distinctiveness-contributing positions in different geographical regions depending on the other variants that previously circulated in those regions. Finally, analysis of Omicron lineages in India and USA shows the BA.1 and BA.2 sub-lineages have comparable distinctiveness, suggesting that they may have similar levels of competitive fitness. Overall, our study proposes that augmenting the ongoing surveillance of highly mutated variants with real-time assessment of Distinctiveness can aid in achieving robust pandemic preparedness.

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