SARS-CoV-2 Beta and Delta variants trigger Fc effector function with increased cross-reactivity

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. [Display omitted] •Fc effector functions are preserved against SARS-CoV-2 variants of concern (VOCs)•Complement deposition against VOCs is reduced more than other functions•VOC infection triggers improved Fc cross-reactivity compared with vaccination•The sequence of the infecting virus determines the breadth of the Fc response Beyond neutralization, antibodies trigger cytotoxic functions associated with SARS-CoV-2 vaccine protection. Richardson et al. show that these functions are retained against variants of concern (VOC) and that infection by VOCs triggers cross-reactive cytotoxic antibodies. This suggests that SARS-CoV-2 VOC could be used as the basis of vaccines triggering enhanced immune breadth.