Dear Dr Low,

Thank you for submitting your manuscript entitled "The role of asymptomatic SARS-CoV-2 infections: rapid living systematic review and meta-analysis" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external assessment.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Richard Turner, PhD

Senior editor, PLOS Medicine

rturner@plos.org

Dear Dr. Low,

Thank you very much for submitting your manuscript "The role of asymptomatic SARS-CoV-2 infections: rapid living systematic review and meta-analysis" (PMEDICINE-D-20-02690R1) for consideration at PLOS Medicine.

Your paper was evaluated by the editors here and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to invite you to submit a revised version that fully addresses the reviewers' and editors' comments. You will appreciate that we cannot make a decision about publication until we have seen the revised manuscript and your response, and we expect to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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 PLOSMedicine@plos.org.

We hope to receive your revised manuscript by Jul 08 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***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.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your 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/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please let me know if you have any questions. Otherwise, we look forward to receiving your revised manuscript soon.

Sincerely,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

-----------------------------------------------------------

Requests from the editors:

As one referee suggests, please update the search.

Please state in some additional detail how you plan to maintain the "living" status of the review.

Please remove the word "rapid" from the title. We suggest adapting the title to: "Development and transmission of asymptomatic SARS-CoV-2 infections: a living systematic review and meta-analysis".

Please add a new final sentence to the "methods and findings" subsection of your abstract, quoting 2-3 of your study's main limitations.

We suggest reversing the order of the two sentences making up the "conclusions" subsection of your abstract.

After the abstract, we will need to ask you to add a new and accessible "author summary" section in non-identical prose. You may find it helpful to consult one or two recent research papers in PLOS Medicine to get a sense of the preferred style.

You may wish to briefly explain what a "shiny app" is.

We would be interested to know whether you see any potential issues in including data from preprints. Would it be possible to report sensitivity analyses omitting these data?

Throughout the text, please add p values alongside 95% CI, where available.

Please adapt reference call outs so that they precede punctuation, e.g. "... a single point [2,3]." (i.e., removing spaces within the square brackets).

Is reference 1 lacking a report number?

Please add the journal details to reference 4.

Where you list preprints in your reference list, e.g., references 25 and 26, please add "[preprint]".

In the attached PRISMA checklist, please refer to individual items by section (e.g., "Methods") and paragraph number rather than by line or page numbers, as the latter generally change in the event of publication.

Comments from the reviewers:

*** Reviewer #1:

Overall comment

This is a timely and well-conducted systematic review addressing an important question. The review follows standard procedures for conduct of a trustworthy review, and the statistical analyses (including subgroups and sensitivity analyses) are appropriate.

I have two main comments.

First, it is claimed in multiple places that this is a"living review" but this is not a living review according to common definitions (including that used by Elliott et al in Plos Medicine). Rather, it appears that the authors created a database that merges 4 other databases and searched it twice. The review itself is important and credible, and there is no need to claim that it is something that it is not (ie living).

Second, living or not, it would be important to update the search prior to publication. I appreciate that this may require considerable work in terms of data extraction and analysis; however, the last search was conducted in mid April and a number of studies have been published since that time.

This review is important and deserves to be reported, but the search and analysis should be updated.

Specific comments

Line 35: "using a living evidence database of SARS-CoV-2 literature" What does this mean

Line 40: Risk of bias was assessed using a questionnaire for modelling studies? Use of a questionnaire to assess bias is unclear? (It is clearer in the text)

Line 61: Substantial disagreement' is claimed by contrasting quotes from a report in mid February and a news article in April. This is journalism and does not belong in a medical journal.

Line 84: There are multiple places where this review is claimed to be a 'living' review but no definition is given and it is unclear what makes this review 'living' other than the fact that the search has been updated at least once (which is common for most reviews).

Line 95: "We searched the covid-19 living evidence database…"

- If I understand correctly, this is a single database that combines records from 4 databases. To me this doesn't fullfil the definition of a "living evidence database" (the same could otherwise be said just about PubMed), and having searched it twice doesn't make this a 'living systematic review'.

*** Reviewer #2:

This manuscript provides a valuable contribution to the COVID-19 literature by summarizing in a "living systematic review" the role of asymptomatic infection in SARS-CoV-2 transmission.

While I have no important concerns about the methods or conclusions, I have a few minor comments. I also wonder if the authors could address in the discussion section a few additional questions that are pertinent:

- Are there relationships among inoculum dose, peak viral load, and likelihood of symptoms? It seems there's a relationship between viral load and infectiousness -- but do we know about this and symptoms? In people or, if no human data, in the macaque infection model?

- Is there evidence to support that the likelihood of symptomatic infection depends on age, comorbidities, or other demographic factors?

Even if we don't have compelling data for these, to what extent might they play a role in the central topics of this manuscript? It might be good to point out in the discussion section types of research beyond the ones reviewed that might inform the manuscript's main topics.

Minor points:

Abstract

Line 47. Might be worth clarifying that the inference that 40-60% of infections from presymptomatic transmission comes from modeling studies fit to data?

Line 50. I'm not sure what 'intermediate' means, or what it's intermediate between. Is there a way to restate this quantitatively?

Discussion.

In the 'implications and unanswered questions' section, it might be worth caveating many of the statements about various interventions that will be needed for controlling transmission. For example, digital contact tracing may not be necessary for control (though in theory it would be helpful) -- it is still unproven in practice.

*** Reviewer #3:

I confine my remarks to statistical aspects of this paper. These were well done and I recommend publication.

Peter Flom

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr. Low,

Thank you very much for re-submitting your manuscript "Asymptomatic SARS-CoV-2 infections: a living systematic review and meta-analysis" (PMEDICINE-D-20-02690R2) for consideration at PLOS Medicine.

I have discussed the paper with editorial colleagues, and it was also seen again by one reviewer. I am pleased to tell you that, provided the remaining editorial and production issues are dealt with, we expect to be able to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

***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.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We hope to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please let me know if you have any questions. Otherwise, we look forward to receiving the revised manuscript shortly.

Sincerely,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

------------------------------------------------------------

Requests from Editors:

Please let us know if you plan to approach updates of this living systematic review in a similar way to that for your previous paper (https://doi.org/10.1371/journal.pmed.1002611; i.e., via an author-maintained dashboard).

We suggest adding "Occurrence of ..." to your title. Also, amending the title to "... asymptomatic and pre-symptomatic ..." would seem worthwhile.

At line 43, please substitute "non-significantly lower".

At line 53 and 78, we suggest substituting "are symptomatic".

We ask you to add a sentence in the methods section of your main text to note that ethics approval was not required for this study.

Please make that "Limitations" at line 346.

Please revisit your reference list. Where appropriate, 6 author names should be listed, followed by "et al".

Comments from Reviewers:

*** Reviewer #3:

I recommended publication of the earlier draft and I still do.

Peter Flom

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Prof. Low,

On behalf of my colleagues and the academic editor, Dr. Nathan Ford, I am delighted to inform you that your manuscript entitled "Occurrence and transmission potential of asymptomatic and pre-symptomatic SARS-CoV-2 infections: a living systematic review and meta-analysis" (PMEDICINE-D-20-02690R3) has been accepted for publication in PLOS Medicine.

PRODUCTION PROCESS

Before publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. When you receive this version you should check and revise it very carefully, including figures, tables, references, and supporting information, because corrections at the next stage (proofs) will be strictly limited to (1) errors in author names or affiliations, (2) errors of scientific fact that would cause misunderstandings to readers, and (3) printer's (introduced) errors.

If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.

PRESS

A selection of our articles each week are press released by the journal. You will be contacted nearer the time if we are press releasing your article in order to approve the content and check the contact information for journalists is correct. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact.

PROFILE INFORMATION

Now that your manuscript has been accepted, please log into EM and update your profile. Go to https://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.

Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Richard Turner, PhD

Senior Editor

PLOS Medicine

plosmedicine.org