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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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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  1. William James

    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.

  2. Sarah Caddy

    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.

  3. This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at

    Does the introduction explain the objective of the research presented in the preprint? Yes The introduction talked about the prevalence of Covid, its different variants, and introduced the experiments of using non neutralizing antibodies, and how it may serve as an effective therapeutic for different SARS-Cov-2 variants
    Are the methods well-suited for this research? Highly appropriate They have appropriate methods on cell culture and antibody production before running any experiments, and they also have very clear specifications for lot numbers of equipment and the source/company of all of necessary items to have run their experiments.
    Are the conclusions supported by the data? Somewhat supported They provide reasonable interpretation of the data, assuming that the data is correct. And they don't concretely say that nnAbs are effective for therapies against different SARS-Cov-2 variants but clarify that their data suggests potential candidates for future therapeutics
    Are the data presentations, including visualizations, well-suited to represent the data? Somewhat appropriate and clear Though their data was clear and seems reasonable to me, they did not have mice models for the newer variants during their paper even though they saw good results for Wuhan strains. Considering that this paper looks at non-neutralizing antibodies as potential therapeutics for current and future strains, I feel as if it would have been most effective to test mice with newer SARS-Cov-2 strains as well
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Somewhat clearly They provide clarity and admit to limitations in their studies and what is expected in future directions of their studies. However their talk of previous work they've done and how their findings change what is already known about SARS-Cov-2 non-neutralizing antibodies is slightly unclear but that could also be due to the fact that I am definitely no expert on the subject
    Is the preprint likely to advance academic knowledge? Moderately likely Though this paper is relevant in that there is a necessity for some change to have continuing effective vaccines as the strains keep changing, the data and conclusions did not seem completely novel. If anything, it was confirmation of previously established findings on non neutralizing antibodies for SARS-Cov-2.
    Would it benefit from language editing? No The paper did not have issues in the way it read. It was clear and was relatively easy to understand.
    Would you recommend this preprint to others? Yes, but it needs to be improved The paper seems almost incomplete, if anything I think there should be inclusion of in vivo work for the mice of newer SARS-Cov-2 variant strains instead of the oldest Wuhan strains. I think that would make the paper more relevant and helpful for potential new therapeutics for SARS-Cov-2
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes Like in the previous question, I firmly believe this paper needs more data such as in vivo work of the newer SARS-Cov-2 strains

    Competing interests

    The author declares that they have no competing interests.