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PONE-D-20-15374

Evaluation of performance of two SARS-CoV-2 Rapid whole-blood finger-stick IgM-IgG Combined Antibody Tests

PLOS ONE

Dear Dr. Guilbot,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 15 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Kwok Hung Chan, Ph.D

Academic Editor

PLOS ONE

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When submitting your revision, we need you to address these additional requirements.

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2.Thank you for including your ethics statement:   "The study was approved by the local Ethics Committee on March 17th 2"020, and informed consent was obtained from each participant."

Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

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3.Thank you for stating the following financial disclosure:

 [Rapid Diagnostic Tests were provided free of charge by AAZ-LMB.].

At this time, please address the following queries:

1. Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.
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3. If any authors received a salary from any of your funders, please state which authors and which funders.
4. If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4.We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

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We will update your Data Availability statement on your behalf to reflect the information you provide.

5. Please amend your authorship list in your manuscript file to include author Angèle Guilbot.

Additional Editor Comments (if provided):

The specificity of the POCT (RDTs) which depends on COVID-19 negative patients by RT-PCR is not enough. The specificity test must be included patients with other respiratory virus infection including human coronaviruses.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Review

This manuscript compares performance of two Point-of-care rapid whole blood finger stick antibody tests for COVID-19. Authors were able to show the performance of these antibody tests (sensitivity and specificity) is good when used after 15 days from onset of symptom

Major Concerns:

1. I have concerns with authors calling COVID-19 antibody tests as “Rapid Diagnostic Tests” (RDTs). WHO, USA CDC, and USA FDA have clearly discouraged using antibody tests as diagnostic tests because of test performance issues and low prevalence of disease. The appropriate way to address these lateral flow antibody tests would be to call them “Point-of-care (POC) tests”.

2. In my opinion, this study is not a “real-life study”, the authors are not studying the effectiveness of intervention (lab results) in “real-life” in the enrolled patients. Authors do not describe how the results of antibody tests were used for providing patient care in this manuscript to qualify as “real-life” study. This study is better characterized as a “Prospective Observational Study”.

Minor Concerns

1. Cover page lists “Angèle Guilbot, Ph.D” as corresponding author and page 1 lists “Thierry Prazuck” as corresponding author. Please verify corresponding author.

2. Please use abbreviations consistently. First use of abbreviation should be spelled out in both abstract and main body separately. Eg. SARS-CoV-2 never spelled out as “Severe acute respiratory syndrome coronavirus 2”. COVID-19 should be spelled out as “coronavirus disease 2019”. RT-PCR should be spelled out as “real-time reverse transcriptase polymerase chain reaction” during first use.

3. Page 3, Line # 92-95:

a. Consider using “antibody tests” instead of “serologic tests” because serologic tests also include antigen tests.

b. Two types of antibody tests are “Point-of-care (POC) tests” (generally lateral flow devices) and “Laboratory tests” (ELISA or chemiluminescent immunoassay tests). Please refer to CDC website for antibody testing classification, https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html.

c. Consider changing “Rapid Diagnostic Tests (RDTs)” to “Point-of-care (POC) tests” (throughout the manuscript).

4. Page 4, line # 113, consider changing “Fingertip blood samples” to “capillary whole blood (WB) sample from fingertip” (throughout the manuscript).

5. Page 4, Line # 136: Consider changing “Rapid Diagnostic Tests” to “Point-of-care (POC) tests” (throughout the manuscript).

6. Page 6, line # 172-175: Consider providing details of average day from symptoms onset (at least average and range).

7. Page 6, line # 192-196: Not sure if authors can draw the conclusion “the IgM were the first antibodies to be detected” from the data provided in Figure 4 and 5. IgG antibodies were present at 0-5 days along with IgM for both COVID-PRESTO® and COVID-DUO®. The % was lower but IgG were not absent at 0-5 days. Also, the number of specimens tested was too small to come to such conclusions.

8. Page 8, line # 239-245:

a. Consider rephrasing the statement “Firstly, as for the assessed RDT, the sensitivity of ELISA tests increases with the duration from symptom onset. Moreover, we showed that direct antibody typing with whole blood is as sensitive as immunoassay performed with serum in a retrospective way.” My understanding is that the authors are trying to say, similar to ELISA tests, the sensitivity of Point of care (lateral flow) antibody tests increases when specimen is collected further from the symptom onset.

b. I disagree with the second point that authors are making “Secondly, these diagnostic tests (either qualitative or quantitative) can help to diagnose a past infection after elimination of the virus by the immune system.” This study does not show diagnostic application of antibody tests. This generalized statement is premature without defining boundaries and criteria for using antibody tests to “diagnose past infections” of COVID-19. Clinical utility of diagnosing past COVID-19 infections is very limited (eg. negative molecular tests in patients presenting late in illness and to establish diagnosis of late complications of COVID-19 illness like Multisystem Inflammatory Syndrome in children) and should be clearly defined before calling antibody tests as “diagnostic tests”.

c. Authors do try to explain use of antibody tests by saying “Thus, combining RT-PCR and antibody detection allows to largely diagnose COVID-19 people regardless of the delay between infection and diagnosis”, but this is till too vague description of its use. This statement is true if antibody tests are used in symptomatic patients only.

9. Page 8, line # 251-253: The results of the study do not show “the switch between the first production of IgM and the later onset of IgG.” As shown in Figure 4 and 5, both IgG and IgM were present throughout the duration from onset of symptoms (0-5 days to >15 days). There was no data provided which showed “seroconversion” or “switch” in patients tested.

10. Page 8, line # 267-269: Consider rephrasing statement “Although slightly lower than the specificity obtained for COVID-PRESTO® and –DUO®, the specificity at early stages was high (91.7%), preventing false positive diagnoses.”

a. Not sure what authors are trying to convey here. Because of high specificity, antibody tests will have low “false positive” diagnosis but more importantly these antibody tests will have significantly high numbers of “false negatives” because of low sensitivity in early stages of disease.

b. Please provide more details of calculations to understand how authors came up with specific of 91.7%. Please also define what does “early stage” means (0-5 days or 0-10 days)?

11. Page 9, line 289-291: Authors say that the antibody tests can be used for “screening” but do not explain screening for what purpose? Screening for diagnosis or immunity or epidemiologic studies, etc.?

12. Page 9, line 292-296: the conclusion is completely different than rest of the manuscript. Throughout the manuscript authors are presenting antibody tests as “diagnostic tests” and then at the end they appropriately limit the use to “assess the response to vaccine candidates and to map levels of immunity in communities”. These two uses are Epidemiologic use of antibody tests and are not considered as “diagnostic use”.

Reviewer #2: This is well written manuscript.

Please change verb responsible (line 68) to causing or similar to omit repeating (previous sentence already has responsible)

My preference would be to use first, second, third etc.(lines 239, 242, 270, 273, 275).

Figure 3 can be omitted

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6. 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: Yes: Gagan Mathur, MD, MBA

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-20-15374R1

Evaluation of performance of two SARS-CoV-2 Rapid IgM-IgG Combined Antibody Tests on capillary whole blood samples from the fingertip

PLOS ONE

Dear Dr. Guilbot,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 10 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Kwok Hung Chan, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Serum samples collected from other respiratory infections can be used to replace blood samples to show the specificity of these two antibody rapid kits. So, the lack of fingertip blood samples from current patients with other respiratory virus infections is a major limitation of this manuscript and should be included in the discussion. This indicates cross-reactivity with other virus infections particularly coronavirus family can’t be excluded.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All concerns satisfactorily addressed by the authors in the revision. Ok to proceed with publication

Reviewer #2: Thank you for addressing all comments. I would suggest final proofread by the native English speaker to address minor things throughout manuscript. Please change COronaVirus disease to coronavirus disease (lines 27, 72)

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7. 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: Yes: Gagan Mathur, MD, MBA

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Evaluation of performance of two SARS-CoV-2 Rapid IgM-IgG Combined Antibody Tests on capillary whole blood samples from the fingertip

PONE-D-20-15374R2

Dear Dr. Guilbot,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Kwok Hung Chan, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: