Abstract:
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VOCs) exhibit escape
from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing
cytotoxic functions of antibodies are associated with improved disease outcome and vaccine protection, Fc
effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with
altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta
VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not
all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc
functions. Furthermore, Beta and Delta infection trigger responses with significantly improved Fc cross-reactivity
against global VOCs compared with D614G-infected or Ad26.COV2.S-vaccinated individuals. This suggests
that, as for neutralization, the infecting spike sequence affects Fc effector function. These data have
important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader
Fc effector responses.
