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Review 1: "A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity"

Published onMar 25, 2022
Review 1: "A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity"
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key-enterThis Pub is a Review of
A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity

SummarySARS-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 decreased disease severity 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 infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either 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.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



This preprint reports on Fc-mediated antibody effector functions targeting different variants of the SARS-CoV-2 spike. The authors studied how these responses were preserved and induced by infections in two different waves of the South African COVID-19 epidemic, dominated by D614G and Beta variants, respectively. This is a timely study that covers an important topic with implications for vaccine design. Overall, the results confirm and advance previous work in the field. It cites current literature and is well-positioned in the current understanding. The authors have adequately addressed ethical concerns and provided ethics approval. The work is well-structured, statistically analyzed, and clearly presented, but some key conclusions are not adequately supported by their findings, which might be roadblocks towards publishing. Furthermore, a more thorough discussion of the limitations of the study is advisable, as explained below.

  • In the second section of the Results, the authors speculate on the higher cross-reactivity of wave 2 responses (“…similar levels of Fc function across the variants tested…, indicating the elicitation of more cross-reactive responses by this VOC.”), but some of these responses, particularly the levels of FcyRIIIa signaling (ADCC) are overall much lower in magnitude in 2nd compared to 1st wave samples, which raises the question of whether these responses are just more balanced (on a lower level), and thus less cross-reactive in the 2nd wave? This concern applies to Figures 2 and 4A, B, and D including the respective text passages, and even the title and the abstract (“Beta infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either D614G infected or Ad26.COV2.S vaccinated individuals.“). Further examples are the last sentence of the Results and also the below-copied sentence in the Discussion, which seem overstated (“We show that, compared to either the original variant or Ad26.COV2.S vaccination, infection with Beta imprints significantly improved Fc cross-reactivity against global VOCs, and that these antibodies target epitopes distinct from those of neutralizing antibodies.”).

  • Regarding the latter sentence: Declaring distinct epitope specificities for antibodies with different functionality appears too speculative based on the given data, and it seems there is a certain overlap of epitopes. As such, the statement in the discussion “Our epitope mapping data indicates that Beta RBD and NTD are not the predominant targets of this function [ADCC]” appears vague in the absence of a direct comparison of the responses with RBD- and NTD-depleted antibody responses. In the same context, the statement in the 3rd section of the Results (“ADCC mediated by wave 1 plasma showed a 2.2 fold decrease against Beta RBD confirming that while K417, E484, and N501 sites are targeted, they do not account for the majority of ADCC activity against the RBD”) is exclusively based on the differential response against D614G and Beta, but epitope specificity was not ultimately assessed in the experiments. It might also be worth mentioning that there is one Beta-defining spike mutation outside of RBD and NTD, i.e., A701V.

  • In the first section of the Results, the authors conclude: “This difference in reduction of binding and neutralizing antibodies confirms the ability of convalescent plasma to target epitopes beyond the neutralizing epitopes mutated in VOCs.” Since neutralization and binding responses were measured in different scales, the obtained data do not ultimately confirm this conclusion. Although the conclusion may eventually be correct, this should be regarded as speculation or hypothesis given the provided data and stated as such.

  • First-wave sequences (presumed D614G viruses) were not confirmed (0/27), and second-wave sequences (Beta) were only partly determined (8/21) (Table S1). Although briefly mentioned in the Results, this limitation should be more thoroughly addressed and discussed, particularly since Figure 1 indicates that Beta viruses might have been present among the first wave sequences already, and D614G and possibly other variants among the second wave sequences. This caveat should also be taken into account in subsequent sections by referring to wave-specific instead of virus-specific responses, for example in the first section of Results (“In contrast, wave 2 plasma from Beta infections…”) or in the second section of Results (“We next measured whether Fc effector functions elicited in response to the original D614G variant or the Beta variant...”).

  • As minor issues, in the introduction, the authors mention three distinct waves in South Africa and continue in the following sentence: “In this study, we leveraged these virologically distinct waves…”. The authors should correct this sentence and state that two of these waves were studied in the current manuscript.

  • In case the authors have access to data describing symptoms/severity of the disease of the hospitalized patients, it would be informative to add since antibody responses differ with the severity of the disease.

  • FcyRIIIa signaling was used as a proxy for ADCC. Although defined in the Methods, it appears more appropriate to report FcyRIIIa signaling instead of ADCC to better differentiate these results from other studies that measured ADCC per se, but this is a decision of the handling editor.

  • In Figure S2F, the term “autologous” should be more clearly defined, which usually refers to the same individual, but here, the authors seem to refer to the spike variant that was dominant in the respective wave.


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