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

Abstract

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 to D614G-infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.

Fc effector cross-reactivity: A hidden arsenal against SARS-CoV-2’s evasive maneuvering

“…The divergence in Fc-effector cross-reactivities of convalescent plasma between the two studies could be due to recruitment of subjects with asymptomatic or mild symptoms 8 versus hospitalized patients. 1 Overall, both studies have provided evidence that cross-reacting non-nAbs continue to interact with emerging VOCs and have the potential to provide immunity against disease despite reductions in neutralizing titers. Further experiments in animal models that focus on protection offered by plasma samples from vaccinated and convalescent individuals against VOCs will clarify the effective contribution of residual Fc-effector activities toward VOC-specific immunity.…”

“…In this issue of Cell Reports Medicine , Richardson et al. 1 investigated these Fc-effector responses using plasma samples from convalescent donors infected during the three distinct waves of COVID-19 infection in South Africa ( Figure 1 ). Each wave was dominated by a different variant (wave 1, D614G; wave 2, Beta; and wave 3, Delta).…”

“…Richardson et al. 1 test Fc-effector functions mediated by patient plasma samples collected during distinct waves of infection in South Africa. Their data shows that prior infection with the Beta variant elicits the broadest Fc effector functions—a finding which may guide future vaccine design.…”

“… 10 Data presented by Richardson et al. 1 suggest that the conformation presented by the Beta VOC spike can be further utilized to generate antibodies with broad Fc-effector function profiles for enhancing SARS-CoV-2 immunity. Moreover, with its constellation of neutralization-resistant mutations, a vaccine based on the Omicron spike may induce broader and durable immune responses to shield us from expected future viral evolution.…”

“…In this issue of Cell Reports Medicine , Richardson et al. 1 show that VOCs differ both in their ability to evade as well as elicit cross-reactive Fc-effector functions.…”