Individual immune selection pressure has limited impact on seasonal influenza virus evolution.

Seasonal influenza viruses are subjected to strong selection as seen by the sequential replacement of existing viral populations on the emergence of new antigenic variants. However, the process of within-host de novo mutant generation and evolutionary selection that underlies these antigenic sweeps is poorly understood. Here, we investigate mutational patterns between evolutionarily closely related human seasonal influenza viruses using host age as a proxy for immune experience. The systematic analysis of >25,000 virus sequences showed that individuals with substantially differing immune histories were frequently (30-62%) infected by viruses with identical amino acid sequences. Viruses from immunologically inexperienced individuals were as likely to possess substitutions with potential phenotypic relevance as highly experienced individuals. Mutations likely to cause antigenic changes were rare among closely related viruses and not associated with extent of host immune experience. These findings suggest that individual immune positive selection plays a limited role in the evolution of seasonal influenza viruses.