PONE-D-22-05585Performance evaluation of the Roche Elecsys Anti-SARS-CoV-2 immunoassays by comparison with neutralizing antibodies and clinical assessmentPLOS ONE

Dear Dr. Tabe

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. The table fonts are very small. The figures are hazy and blurry. The abstract should include detailed results with number. Please correct and resubmit

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PONE-D-22-05585R1Performance evaluation of the Roche Elecsys Anti-SARS-CoV-2 immunoassays by comparison with neutralizing antibodies and clinical assessmentPLOS ONE

Dear Dr. Tabe,

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. Bothe reviewers has serious concerns about the methodology. Further Rev2 believes that the manuscript is poorly written and organized. Please make sure that you address all of comments of the reviewers before you submit  a revised version.   

Please submit your revised manuscript by Jun 23 2022 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.

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• 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'.
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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.

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We look forward to receiving your revised manuscript.

Kind regards,

Gheyath K. Nasrallah

Academic Editor

PLOS ONE

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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: (No Response)

Reviewer #2: (No Response)

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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: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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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: No

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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: No

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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: Takei et al. investigated the correlation between the neutralizing antibody titre measured by two commercially available immunoassays and a standard virus neutralization assay. The measurement values of Elecsys Anti-SARS-CoV-2 S and neutralization assays were highly correlated and significantly higher values has been measured in the group of severe and critically ill cases. The study is of interest as serological tests are essential tools to evaluate the neutralizing antibodies targeting the receptor binding domain of the SARS-CoV-2 spike protein.

The authors might consider some minor comments:

Section Materials and methods, Neutralization assay:

It would be interesting to read which strain of SARS-CoV-2 was used in the assay, as the neutralizing activity of the antibodies may be different against the original SARS-CoV-2 strain and the emerging variants of concern. There may be differences between the neutralizing antibody titer measured by the commercially available immunoassays and the protective immunity, depending on the viral variant.

Section Results, Table 3:

Is there any information available regarding the SARS-CoV-2 vaccination status of these patients? Or they were all immunologically naïve prior to the acute infection?

In addition to the diagnostic PCR assays, has a variant determination been performed in the study group?

Reviewer #2: In this study, the authors investigated whether measuring anti-SARS-CoV-2 Spike antibodies can predict neutralizing activities in patients’ sera. A commercial assay (Elecsys® Anti-SARS-CoV-2) was utilized for measuring anti-S and anti-N SARS-CoV-2 antibodies. This was then compared to neutralizing titers utilizing an authentic virus neutralization assay.

Major comments:

1- The article is poorly written. All sections need to be improved. There are missing info in the abstract and methods. The authors did not discuss similar studies nor compared their results to literature in their discussion.

2- A major concern in the study in the correlation analysis. The authors indicated that 146 serum samples were tested, with a positivity rate of >70% for both binding and neutralization assays. However, the correlation figures (Fig 1A and 1B) included only few data points (n=6). All data points (n=146) need to be plotted along with a properly drawn fitted line, in addition, r, and r2 values need to be both mentioned in order to assess the strength of the correlation.

3- The abstract needs to be improved. The numbers and percentages need to be added accordingly with each finding.

4- Patients sample details needs to be better described in the Methods section. There is no information on how many samples were collected per patient. What is the number of inpatients and outpatients? Also, what is the duration between different time-points?

5- Figures and legends are poorly presented. Please fix the following:

a.Figure 1 needs re-plotting after including all the results.

b.In figure 2, better to label the lower panels with other labels (E,F and G), better than referring to them as “the lower panel of panel A, B or C”

c.Figure 3 is not clear at all. It is better to use colors to differentiate between patients.

d.In figure 3, why did they choose patients who were tested more than 3 time points only? Patients with 3 time-points can be included in the analysis especially if there is a good time gap between each time-point.

e.All legends need to be expanded to clearly indicate the type of test, analysis, and sample numbers.

6- In line 260, it is mentioned: “no significant reduction in antibody levels tested was observed until 69 days after the onset of symptoms”. I believe this was observed in 2 patients only whose samples were available at that time-point. This is not enough to draw conclusions. The limitation of sample size need to be clearly mentioned in the discussion.

Minor comments:

1- In the abstract, change "levels of neutral antibodies in COVID-19" to "neutralization antibodies"

2- The catalog numbers of the used commercial assays need to be mentioned in the methods.

3- Kindly indicate the type/source of the real virus used in the neutralization assay.

4- In the methods section, it is better to change “Clinical Backgrounds” to “Clinical characteristics”.

5- Table 1. If age is represented as range, please add this to the label of the row “Age range (average)”

6- Whenever “Elecsys® Anti-SARS-CoV-2” is mentioned, it is better to add “anti-N”, so it does not confuse the reader. This applies to figures and tables too.

7- Table 1 and 3 have the same title. Kindly change the title of table 3 to “inpatients”.

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Reviewer #1: No

Reviewer #2: Yes: Maria K. Smatti

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Performance evaluation of the Roche Elecsys ® Anti-SARS-CoV-2 immunoassays by comparison with neutralizing antibodies and clinical assessment

PONE-D-22-05585R2

Dear Dr. Tabe,

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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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Gheyath K. Nasrallah

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #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 #2: Yes

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

Reviewer #2: Yes

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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 #2: Yes

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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 #2: Yes

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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 #2: (No Response)

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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 #2: No

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