Waning immunity drives respiratory virus evolution and reinfection.

Viruses differ in the number and types of host tissues in which they replicate. For example, systemically replicating viruses such as measles infect cells and tissues throughout the body, whereas respiratory viruses such as influenza viruses and coronaviruses replicate only in the respiratory tract. Reinfections with respiratory viruses are thought to be driven by ongoing antigenic immune escape in the viral population. However, this does not explain why antigenic variation is frequently observed in respiratory viruses and not systemically replicating viruses. Here, we argue that the rapid rate of waning immunity in the respiratory tract is a key driver of antigenic evolution in respiratory viruses. Waning immunity results in hosts with immunity levels that protect against homologous reinfection but are insufficient to protect against infection with an antigenically different (heterologous) strain. Thus, when partially immune hosts are present at a high enough density, an immune escape variant can invade the viral population even though that variant cannot infect solidly immune hosts. Invasion can occur even when the variant's immune escape mutation incurs a fitness cost, although any such cost is likely to be short-lived from compensatory evolution. Thus, the mutant lineage may replace the wild type and, as immunity to it builds, the process will repeat. Our model provides a new explanation for the pattern of successive emergence and replacement of antigenic variants that has been observed in many respiratory viruses. We discuss our model relative to others for understanding the drivers of antigenic evolution in respiratory viruses.