Dear Professor Cuevas,

Thank you very much for submitting your manuscript "Prevalence of neutralising antibodies against SARS-CoV-2 in acute infection and convalescence: a systematic review and meta-analysis" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the 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).

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Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. 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,

Tao Lin, DVM, MSc

Associate Editor

PLOS Neglected Tropical Diseases

Liesl Zuhlke

Deputy Editor

PLOS Neglected Tropical Diseases

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The study is clearly articulated and the objectives well described. The design is appropriately set for a study that is needed in the field. The studies selected are often small and a larger size would benefit however the analysis provides clear conclusions using well established methodology.

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The analysis presented match the analysis plan. The neutralizing antibody results are clearly and well presented.

The IgG analysis comes with a lot of complexity is lacking granularity.

Reviewer #2: (No Response)

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The conclusions are supported great deal by the data presented and the limitations of analysis are described. The authors discuss how these data are helpful to advance our understanding of the neutralizing antibody immunity against SARS-CoV2. However, larger studies are needed to be able to address the relevance for public health recomendations.

Reviewer #2: (No Response)

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Results

THe IgG/nAntibodie association analysis needs differentiation between different viral antigen or limit it to the surface antigen against which the neutralizing antibodies are directed against.

Discussion

“The lack of neutralising antibodies in a small but significant group of patients might be explained by some patients having responses confined to other SARS-CoV-2 antigens or mediated through T cells, which are not detected by the neutralisation assays in this meta-analysis.” It is not clear who those groups of patients are.

“Mild infections may also elicit responses that are restricted to the mucosal cells, where defence responses are dominated by the secretory immune system.” Interesting statement and good hypothesis that is not evidenced.

“The proportion of participants with neutralising antibodies in the second month was slightly higher among plasma donors and slightly lower among patients recruited from hospital. However, the differences were small and confidence intervals overlapped.

Moreover, neutralising antibodies peak within 21 days after symptoms onset and the one month is not ideal to demonstrate time differences” Do you mean that antibodies in hospitalized individuals might decline faster? Do the responses peak within 21 days for both groups?

Reviewer #2: none

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The authors describe a meta analysis of published studies describing the neutralising antibody titres induced by SARS-CoV 2 acute infection. This is an important study considering the need to understand corelates of immunity by both infection and vaccination. Furthermore, increasing evidence is arguing for the role of neutralizing antibodies. One element that is clearly understood throughout the study is the lack of large cohort comprehensive studies to establish this fact. Only very few studies could be retained for the analysis amongst large number of publications initially selected. None the less the analysis is well conducted, and the authors conclude that the disease severity is largely correlating with the levels of neutralizing antibodies induced.

There are differences between neutralization assay sensitivity that also show throughout the study and it is unclear to what degree it will affect the analysis.

The authors have investigated the associations between neutralizing antibody titres and the Elisa IgG titres. This part of the study has some weakens as besides the neutralising antibody assay variation the binding antibody assays can also be very variable. The type of assay used and most of all the origin of recombinant antigen utilised will influence the assay a great deal. In addition, table 1 indicates a variety of viral antigens utilised to measure IgG and the study lacks granularity.

Reviewer #2: (No Response)

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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.

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Attachments

Attachment

Submitted filename: PNTD-D-21-00266 review.docx

Dear Professor Cuevas,

We are pleased to inform you that your manuscript 'Prevalence of neutralising antibodies against SARS-CoV-2 in acute infection and convalescence: a systematic review and meta-analysis' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

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 Neglected Tropical Diseases.

Best regards,

Tao Lin, DVM, MSc

Associate Editor

PLOS Neglected Tropical Diseases

Liesl Zuhlke

Deputy Editor

PLOS Neglected Tropical Diseases

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

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #2: Yes

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #2: Yes

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #2: Yes

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #2: (No Response)

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #2: (No Response)

**********

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 #2: No