James (Jim) J Bull

Current theory for the regulation of host populations by pathogens suggests that a high level of suppression during the initial epidemic phase will be followed by a population rebound with decreased virulence due to pathogen and host evolution, and the extent of host suppression increases with increasing pathogen transmissibility (R0) and virulence. Using simple epidemiological models, we explore the effect of three factors on short- and long-term suppression: the strength of density-dependent population regulation (homeostasis); maternal antibodies, and age-dependent mortality. Rapid homeostasis can mitigate long-term population suppression, and surprisingly weak homeostasis can even result in a greater population suppression during the endemic phase compared to the initial epidemic. Maternal antibodies can significantly reduce suppression of the host population if they attenuate rather than block infections. A similar result obtains if the severity of disease is lower in the young than in adults. In both cases, a higher R0 can result in lower suppression, and the average virulence can decline over time without any (genetic) evolution. Our results suggest the need for a nuanced view of long-term suppression by a new pathogen, with the outcome sensitive to many details even in the absence of evolution.

Reinfections with respiratory viruses such as influenza viruses and coronaviruses 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 these viruses relative to viruses such as measles that undergo systemic replication. Here, we suggest that the rapid rate of waning immunity in the respiratory tract is the 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 a heterologous, antigenically different strain. As such, 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 fully immune hosts. Invasion can occur even when the variant's immune escape mutation incurs a fitness cost, and we expect the expanding mutant population will evolve compensatory mutations that mitigate this cost. Thus the mutant lineage should 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 testable predictions of our model relative to others for understanding the drivers of antigenic evolution in these and other respiratory viruses.Reinfections with respiratory viruses such as influenza viruses and coronaviruses 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 these viruses relative to viruses such as measles that undergo systemic replication. Here, we suggest that the rapid rate of waning immunity in the respiratory tract is the 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 a heterologous, antigenically different strain. As such, 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 fully immune hosts. Invasion can occur even when the variant's immune escape mutation incurs a fitness cost, and we expect the expanding mutant population will evolve compensatory mutations that mitigate this cost. Thus the mutant lineage should 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 testable predictions of our model relative to others for understanding the drivers of antigenic evolution in these and other respiratory viruses.