Agent-based modeling and phylogenetic analysis suggests that COVID-19 will remain a low-severity albeit highly transmissible disease

The ongoing COVID-19 pandemic is still producing hundreds of thousands of cases worldwide. However, the currently dominant Omicron variant (and its sub-variants) have proven to be less virulent than previous dominant variants, resulting in proportionately fewer severe cases, hospitalizations and deaths. Nonetheless, a persistent concern is that new mutations of the SARS-CoV-2 virus may yet produce more virulent variants. In the present study we provide evidence supporting the hypothesis that this is unlikely, and that COVID-19 will remain a low-severity although highly transmissible disease. Three complementary pieces of evidence support our argument. First, empirical observations suggest that the transmission advantage that Omicron (sub)variants enjoy is in large part due to their cell tropism in the upper respiratory tract, which renders them less virulent. Second, when a negative link between transmissibility and virulence is included in agent-based epidemiological models, viruses evolve towards lower virulence. Third, genetic diversification of SARS-CoV-2 suggests that epistasis in the Omicron family reduces the diversity of successful variants. Taken together these observations point to a high likelihood that the severity of COVID-19 will remain sufficiently low for an endemic status to be reached, provided that vaccination campaigns and sensible hygiene and social measures continue worldwide, as suggested by the World Health Organization.