Abstract
Despite the propensity for complex and non-equilibrium dynamics in nature, eco-evolutionary analytical theory typically assumes that populations are at equilibria. In particular, pathogens often show antigenic escape from host immune defences, leading to repeated epidemics, fluctuating selection and diversification, but we do not understand how this impacts the evolution of virulence. We model the impact of antigenic drift and escape on the evolution of virulence in a generalized pathogen and apply a recently introduced oligomorphic methodology that captures the dynamics of the mean and variance of traits, to show analytically that these non-equilibrium dynamics select for the long-term persistence of more acute pathogens with higher virulence. Our analysis predicts both the timings and outcomes of antigenic shifts leading to repeated epidemics and predicts the increase in variation in both antigenicity and virulence before antigenic escape. There is considerable variation in the degree of antigenic escape that occurs across pathogens and our results may help to explain the difference in virulence between related pathogens including, potentially, human influenzas. Furthermore, it follows that these pathogens will have a lower R0, with clear implications for epidemic behaviour, endemic behaviour and control. More generally, our results show the importance of examining the evolutionary consequences of non-equilibrium dynamics.