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Review 1: "Protective Non-neutralizing mAbs Ab94 and Ab81 Retain High-affinity and Potent Fc-mediated Function Against SARS-CoV-2 Variants from Omicron to XBB1.5"

Overall, the reviewers caution against strong conclusions without additional confirming data.

Published onDec 14, 2023
Review 1: "Protective Non-neutralizing mAbs Ab94 and Ab81 Retain High-affinity and Potent Fc-mediated Function Against SARS-CoV-2 Variants from Omicron to XBB1.5"
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Protective non-neutralizing mAbs Ab94 and Ab81 retain high-affinity and potent Fc-mediated function against SARS-CoV-2 variants from Omicron to XBB1.5
Protective non-neutralizing mAbs Ab94 and Ab81 retain high-affinity and potent Fc-mediated function against SARS-CoV-2 variants from Omicron to XBB1.5
Description

Abstract Antibodies play a central role in the immune defense against SARS-CoV-2. There is substantial evidence supporting that Fc-mediated effector functions of anti-spike antibodies contribute to anti-SARS-Cov-2 immunity. We have previously shown that two non-neutralizing but opsonic mAbs, Ab81 and Ab94, are protective against lethal Wuhan SARS-CoV-2 infection in mice. The protective effect was comparable to a potent neutralizing antibody, Ab59. Here, we hypothesized that, unlike the neutralizing antibodies, non-neutralizing opsonic antibodies would have a higher likelihood of retaining their function to the mutated variants, potentially functioning as broadly protective mAbs. Most of the mutations on the SARS-CoV-2 variants cluster on neutralizing epitopes, leaving other epitopes unaltered. We observed that neutralizing antibodies lost binding to Omicron. In contrast, seven non-neutralizing opsonic antibodies retained nanomolar affinity towards Omicron, BA.2, BA.4, and BA.5. Focusing on the two protective non-neutralizing antibodies Ab81 and Ab94, we showed that they maintain their strong reactivity even to XBB, XBB1.5, and BQ1.1. In the case of Ab94, interestingly, it even has increased affinity towards all variants except for XBB, which is comparable to WT. Finally, we show that Ab94 and Ab81 have potent Fc-mediated functions in vitro against the XBB and BQ1.1 and that combining the mAbs in a cocktail further enhances the effect. These results show that protective non-neutralizing mAbs such as Ab94 and Ab81 can be a viable strategy for anti-SARS-CoV-2 mAb therapies against current and possibly future SARS-CoV-2 variants and that opsonic epitopes could have implications for vaccine design.

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.

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Review:

This study investigates binding and phagocytosis induction by non-neutralizing Spike-specific monoclonal antibodies (mAbs) in vitro in the presence of different variants of SARS-CoV-2. The authors explain that many Spike-specific mAbs that can neutralize and protect against the earlier variants of SARS-CoV-2 are no longer effective against the more recent variants. This poses a significant challenge therapeutically. The authors demonstrate that their non-neutralizing mAbs are more effective at inducing phagocytosis in vitro that neutralizing mAbs. They conclude that non-neutralizing mAbs could be a viable therapeutic strategy against variant strains.

Methods used are appropriate and robust, with the results from each set of experiments presented well in each figure.

It would be useful to place more emphasis on the fact that all experiments in this manuscript are in vitro. Without any in vivo experiments, it is not possible to make firm conclusions about any of the likely therapeutic effects for newer variants. I agree that this data is promising, but it is recommended that language is edited accordingly e.g. final sentence of abstract change ‘can’ to ‘could’.

Figure 3 presents the results of the THP1-based phagocytosis assays, showing the two non-neutralizing antibodies have a greater phagocytosis score for BQ1.1 and XBB variants than a control IgG specific for IgE. The authors state that the antibodies they are studying mediate ‘potent’ Fc-mediated function, but this is difficult to judge from the data presented where everything is relative to a non-specific control. It would be interesting to see a comparison with phagocytosis induced against earlier SARS-CoV-2 variant spike proteins. This would enable a more accurate comparison with the in vivo data mentioned from previously published work. The phagocytosis scores here are difficult to interpret without knowing which score correlated with protection when a different strain was used.

Minor comment:

  • Are you using the word ‘opsonic’ to simply mean binding ability? I suggest editing this to make it clearer to readers e.g.  ‘antibodies were non-neutralizing but capable of binding spike and triggering phagocytosis’.

  • For consistency it would be good to see the Associated beads (MFI) results for the XBB data presented in L.

  • In Figure 3 legend, please clarify which variant each assay is studying.

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