Skip to main content
SearchLoginLogin or Signup

Review 2: "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 2: "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"
1 of 2
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.

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.

***************************************

Review:

The field of evaluating monoclonal antibodies to SARS-CoV-2 spike is now extensive, going back over 3 years. This manuscript adds incrementally to the literature but generally confuses rather than clarifies. If the true focus of the work was (as I thought originally) to prove that Fc effector functions, such as phagocyte opsonization, were quantitatively important in protection from infection, pathology and/or transmission, then it fails in this task. This is a pity, as the question is valid and important. I will restrict my further comments to this aspect, as I feel the observations relating to other topics neither address compelling questions nor provide convincing evidence.

Ideally, the work would have looked at both potently neutralizing (NT50<<100 nM) mAb to a range of well-characterized sites on spike (see below) and compared their properties to those of equivalent affinity but non-neutralizing antibodies to nearby epitopes. Plenty of examples are already described. Neutralizing epitopes would include the RBD Class 1 and 2 antibodies (that overlap with the mutable ACE2 binding site), Class 3 &4 (non-ACE-2 competing, on the RBD flanks), NTD and S2. Only if they could demonstrate the new reagents described here offered experimental advantages for the main hypothesis test over these ought they be included.

To test whether Fc effector functions specifically are implicated in the phenotypic readouts (especially in vivo protection), then the authors should use PCR-nonbinding mutant derivatives in parallel (Lala, STR, etc). Without this control, I would draw no conclusions.

The argument that non-neutralizing antibodies are important in protection *because* their epitopes do not show escape mutation in the field is somewhat irrational. If they worked by reducing viral replication through Fc effector functions in vivo, they would exert the same sort of selection pressure for escape mutations as neutralizing antibodies! The more subtle point could be that such antibodies could provide valuable protection from serious disease (perhaps by facilitating clearance before descent to the alveoli) but without inhibiting replication in the upper airways and therefor onward transmission) is, however, reasonable, and should be made more clearly.

On a minor point, I did not understand the nature of the challenge virus in the in vivo experiment. They call it "Wuhan strain from Swedish isolate". If they mean a specific isolate from Sweden during the first wave, it is likely a B.1 (D614G) rather than Wuhan-1 (B). The formal lineage information ought to be provided, as it is very relevant to this sort of work.

Comments
0
comment
No comments here
Why not start the discussion?