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Reviews of "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"

Reviewers: S Caddy (Cornell) | 📒📒📒◻️◻️ • W James (University of Oxford) | 📒📒📒◻️◻️

Published onDec 14, 2023
Reviews of "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"
key-enterThis Pub is a Review of
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.

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Summary of Reviews: Both reviewers find the preprint's in vitro evidence for SARS-CoV-2 antibody enhancement of dengue infection potentially informative but one reviewer offers criticism on the lack of controls, specificity of the results, and details needed to interpret the findings, while the other cautions against drawing conclusions without further in vivo evidence supporting relevance to human infections. Overall, they caution against strong conclusions without additional confirming data.

Reviewer 1 (Sarah C…) | 📒📒📒 ◻️◻️

Reviewer 2 (William J…) | 📒📒📒 ◻️◻️

RR:C19 Strength of Evidence Scale Key

📕 ◻️◻️◻️◻️ = Misleading

📙📙 ◻️◻️◻️ = Not Informative

📒📒📒 ◻️◻️ = Potentially Informative

📗📗📗📗◻️ = Reliable

📘📘📘📘📘 = Strong

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