Coordinated immune response distinguishes duration of SARS-CoV-2 viral particle shedding in humans

SARS-CoV-2 acquisition induces a spectrum of COVID-19 disease severity and duration among people. Prolonged viral antigen shedding (PVS) is defined as when a person tests positive by direct antigen tests performed a minimum of 21 days apart. It is unclear why some people exhibit delayed SARS-CoV-2 viral antigen clearance. In this cross-sectional observational study enrolling vaccine naive adults from the USA and Peru following recovery from SARS-CoV-2 acquisition, we examined a suite of blood-derived immune measures to understand differences between participants with PVS (n = 36) and without PVS (non-PVS, n = 223). While PVS participants demonstrated lower overall SARS-CoV-2-specific antibody magnitudes, over-representation analysis revealed that immune feature magnitude alone could not fully explain cohort differences. Hierarchical clustering and network analyses identified more highly coordinated antibody responses, T cell activation, and Fc-mediated function among non-PVS compared to PVS participants. These findings link control of viral antigen shedding to a coordinated immune response.