Persistent infections in immunocompromised hosts are rarely sources of new pathogen variants.

Many viruses, including human norovirus and influenza, cause self-limiting diseases of short duration. However, infection by the same viruses in an immunocompromised host can result in prolonged illness in the absence of effective treatment. Such persistent infections are often characterized by increased genetic diversity with potentially elevated rates of evolution compared to acute infections, leading to suggestions that immunocompromised hosts represent an important reservoir for the emergence of novel viral variants. Here, we develop a mathematical model that combines epidemiological dynamics with within-host evolution to quantify the relative contribution of immunocompromised hosts to the overall rate of pathogen evolution. Using human norovirus as a case study we show that the majority of evolutionary substitutions are expected to occur in acute infections of immunocompetent hosts. Hence, despite their potential to generate a high level of diversity, infections of immunocompromised hosts likely contribute less to the evolution and emergence of new genetic variants at the epidemiological scale because such hosts are rare and tend to be isolated. This result is robust to variation in key parameters, including the proportion of the population immunocompromised, and provides a means to understand the adaptive significance of mutations that arise during chronic infections in immunocompromised hosts.