https://orcid.org/0000-0003-1361-4151
Peer Review History
| Original SubmissionSeptember 30, 2020 |
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Dear Dr. Freund, Thank you very much for submitting your manuscript "Multi-Clonal SARS-CoV-2 Neutralization by Antibodies Isolated from Severe COVID-19 Convalescent Donors" for consideration at PLOS Pathogens. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations. The reviewers have identified some issues that should be addressed. Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. When you are ready to resubmit, please upload the following: [1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out [2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file). Important additional instructions are given below your reviewer comments. Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments. Sincerely, Kanta Subbarao Section Editor PLOS Pathogens Kanta Subbarao Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************** The reviewers have identified some issues that should be addressed. Reviewer Comments (if any, and for reference): Reviewer's Responses to Questions Part I - Summary Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship. Reviewer #1: Mor and colleagues investigate the antibody response in COVID patients comparing those with mild and severe symptoms. Their findings from plasma analysis confirm recent reports that severe cases have more IgG antibodies and more virus neutralizing activity. Molecular analysis of antibody sequences identified some VHJH that were enriched in COVID infected individuals, and two sequences that were uniquely overexpressed in the severe group. Recombinant antibodies to the RBD were derived from two patients and characterized. They recognize distinct epitopes on RBD and are neutralizing. Several groups have recently reported on the antibody response and on monoclonal antibodies to SARS-CoV-2, which diminishes the novelty of the findings. Nevertheless, the experiments and analyses are of very high quality and importance, carefully reported, and important to the field. Rigorous methodology was applied. Reviewer #2: This is a well-written manuscript describing the isolation and characterisation of SARS-CoV-2 neutralizing antibodies from infected individuals. The authors use the RBD to select B cells. Sequence analysis of SARS-CoV-2 specific mAbs are used to analyze the clonality of the immune response and are compared to those of “non-covid” individuals. Below are some points that need to be addressed. This is a timely study and adds to the body of research on Ab responses to SARS-CoV-2 infection. ********** Part II – Major Issues: Key Experiments Required for Acceptance Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions. Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject". Reviewer #1: Two major issues: - Antibodies are made of heavy and light chains (H and L). Particular VHJH sequences were found to be enriched in COVID patients. The same analysis should be performed for the light chains, and if possible for the heavy and light chains combined. - It is stated that ‘data are available with no restrictions’ but could not find table with all antibody sequences related to Figure 2, and the full sequence of the cloned monoclonal antibodies is missing. This information should be included. Reviewer #2: (No Response) ********** Part III – Minor Issues: Editorial and Data Presentation Modifications Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. Reviewer #1: - ‘live SARS-CoV-2’: presumably the authors mean ‘authentic SARS-CoV-2’ as opposed to pseudo virus, consider re-wording - first part of the introduction could be improved - third paragraph of the results: the main text should explain how the RBD positive cells were identified - Figure 7 is hard to interpret - Discussion: “Severe donors had higher level of shared B cell closed(?) compared to…” - many have shown the effects of combination therapy (e.g. Regeneron antibodies) so the following should be modified or removed: “This is the first demonstration that combinations of neutralizing anti-SARS-CoV-2 nAbs can effectively block the spread of live SARS-CoV-2” Reviewer #2: The authors discuss pre-existing immunity to HCoV and cross-reactivity between SARS-CoV-2 in the first section of the results. However, they are using samples collected after SARS-CoV-2 infection so this section should be changed to take this into account. The authors isolate B cells binding to the RBD bait and analyze the sequences generated. However, in the downstream analysis it appears that not all the expressed mAbs bind to S. What do the authors think is the reason for this? If they are false positives in the sorting step then these sequences should not be included in the sequence analysis. This needs to be addressed in the text. It is not clear how the 9 and 13 mAbs from donors CoV01 and CoV02 were selected for further analysis. This should be clarified in the text. In figure 6b and 6c, the mAb alone (1109 or 2212) at 2ug/mL or 20ug/mL should be shown on the graph to compare with the combinations of mAbs and better show the synergistic effects. Is it not expected that the Ab response would be multi-clonal? Many other studies have shown that there are several neutralizing epitopes on S. These papers should be referenced in the discussion section. The authors highlight that some individuals with mild COVID-19 do not produce anti-RBD-IgG that could inhibit RBD:ACE2 interaction. Do these donors have neutralizing serum? If yes, would this not suggest that they produce nAbs targeting the other neutralizing epitopes identified? In the final paragraph of the discussion, the authors conclude that this is the first study to show combinations of mAbs can block spread of live SARS-CoV-2. However, the data for a mAb on its own is not shown for comparison. The relevance of this observation should be included within the discussion. Why is the spreading assay more relevant than a neutralization assay for example? Other labs have also tried combinations and these should be referenced/discussed. More references are required to other studies on SARS-CoV-2 Ab responses are needed. In particular the part referring to the relationship between disease severity and magnitude of the Ab response. Page 7: what was the potency of the live virus neutalization compared to the pseudovirus? Page 7: TAU-2212 does not bind S in ELISA but does on the cell surface and has neutralizing activity. The authors suggest it may be binding an epitope involving more than one subunit. The authors do not state what form the S is that is used in ELISA. Is it a stabilised trimer? Page 9: The data presented does not justify the conclusion that “these nAbs can be produced by the majority of individuals”. “may” would be more appropriate. ********** PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Figure Files: While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Data Requirements: Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5. Reproducibility: To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plospathogens/s/submission-guidelines#loc-materials-and-methods |
| Revision 1 |
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Dear Dr. Freund, We are pleased to inform you that your manuscript 'Multi-Clonal SARS-CoV-2 Neutralization by Antibodies Isolated from Severe COVID-19 Convalescent Donors' has been provisionally accepted for publication in PLOS Pathogens. Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests. Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated. IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript. Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS. Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Kanta Subbarao Section Editor PLOS Pathogens Kanta Subbarao Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************************************************** Reviewer Comments (if any, and for reference): |
| Formally Accepted |
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Dear Dr. Freund, We are delighted to inform you that your manuscript, "Multi-Clonal SARS-CoV-2 Neutralization by Antibodies Isolated from Severe COVID-19 Convalescent Donors," has been formally accepted for publication in PLOS Pathogens. We have now passed your article onto the PLOS Production Department who will complete the rest of the pre-publication process. All authors will receive a confirmation email upon publication. The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Pearls, Reviews, Opinions, etc...) are generated on a different schedule and may not be made available as quickly. Soon after your final files are uploaded, the early version of your manuscript, if you opted to have an early version of your article, will be published online. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers. Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens |
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