Background: While pathogens often evolve towards reduced virulence, many counterexamples are evident. When faced with a new pathogen, such as SARS-CoV-2, it is highly desirable to be able to forecast the case fatality rate (CFR) into the future. Considerable effort has been invested towards the development of a mathematical framework for predicting virulence evolution. Although these approaches accurately recapitulate some complex outcomes, most rely on an assumed trade-off between mortality and infectivity. It is often impractical to empirically validate this constraint for human pathogens. Results: Using a compartment model with parameters tuning the degree to which symptomatic individuals are isolated and the duration of immunity, we reveal kinetic constraints where the variation of multiple parameters in concert leads to decreased virulence and increased pathogen fitness, whereas independent variation of the parameters decreases pathogen fitness. Smallpox, SARS-CoV-2, and Influenza are analyzed as diverse representatives of human respiratory viruses. We show that highly virulent viruses, such as Smallpox, are likely often constrained by host behavior, whereas moderately virulent viruses, such as SARS-CoV-2, appear to be typically constrained by the relationship between the duration of immunity and CFR. Conclusions: The evolution of human respiratory epidemics appears to be often kinetically constrained and a reduction in virulence should not be assumed. Our findings imply that, without continued public health intervention, SARS-CoV-2 is likely to continue presenting a substantial disease burden. The existence of a parameter regime admitting endemic equilibrium suggests that herd immunity is unachievable. However, we demonstrate that even partial isolation of symptomatic individuals can have a major effect not only by reducing the number of fatalities in the short term but also by potentially changing the evolutionary trajectory of the virus towards reduced virulence.
Evolution of Human Respiratory Virus Epidemics