Peer Review History

Original SubmissionDecember 5, 2019
Decision Letter - Amal Al-Bakri, Editor

PONE-D-19-33702

Radioimmunotherapy of Methicillin-resistant Staphylococcus aureus in planktonic state and biofilms

PLOS ONE

Dear Dr  Dadachova Ekaterina

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.

Though the manuscript is presented as a proof of concept, we recommend that the potential toxicity of such treatment to be highlighted in the manuscript. Accordingly, you are advised to modify the manuscript highlighting this limitation and resubmit .

We would appreciate receiving your revised manuscript by Feb 22 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable 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/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
  • A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
  • An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled '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.

We look forward to receiving your revised manuscript.

Kind regards,

Amal Al-Bakri

Academic Editor

PLOS ONE

Additional Editor Comments:

Dear Authors,

Though the manuscript is presented as a proof of concept, we recommend that the potential toxicity of such treatment to be highlighted in the manuscript. Accordingly, you are advised to modify the manuscript highlighting this limitation and resubmit .

Regards

Journal Requirements:

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

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In your Methods section, please give the sources of any bacterial strains used in your study.

3. 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.

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5. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

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"This research was funded by Health Holland"

We note that you received funding from a commercial source: Health Holland

a. Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc.

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[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Revision 1
Decision Letter - Amal Al-Bakri, Editor

PONE-D-19-33702R1

Radioimmunotherapy of Methicillin-resistant Staphylococcus aureus in planktonic state and biofilms

PLOS ONE

Dear Dr Dadachova

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.

Specifically, reviewer recommends more experimental work to be done.

We would appreciate receiving your revised manuscript by May 30 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable 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/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
  • A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
  • An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled '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.

We look forward to receiving your revised manuscript.

Kind regards,

Amal Al-Bakri

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

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

**********

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: This manuscript expands on the growing repertoire of immunotherapy applications, outside of cancer. The authors have provided a proof-of-concept study investigating radioimmunotherapy for the treatment of Methicillin-resistant staphylococcus aureus. As such, rigorous experimentation as been performed and the data provided is sufficient. This research indeed contributes to a gap in the field of therapeutic options for prosthetic joint infection (PJI) and offers a novel approach. No additional revision is required, as authors have adequately addressed the comments of previous reviewer. Furthermore, this manuscript adheres to PLOS ONE criteria.

Reviewer #2: The authors have addressed the issues raised in the previous review. However, there is little innovation here. It is not clear that there is a specific antibody effect and whatever was observed would be expected. An in vivo study would generate more interest.

**********

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: Dr. Krupa Naran

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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Reviewer 1

Though the manuscript is presented as a proof of concept, we recommend that the potential toxicity of such treatment to be highlighted in the manuscript. Accordingly, you are advised to modify the manuscript highlighting this limitation and resubmit.

Response: We have added the following paragraph and additional references 12-15 to the revised manuscript. The paragraph reads: “Previously we have performed extensive evaluation of RIT toxicity in mouse models of fungal and bacterial infections using the antibodies labeled with the same 213Bi radionuclide utilized in this work. No systemic toxicity was noted in mice infected with Streptococcus pnemoniae and treated with 213Bi-labeled antibody to bacterial polysaccharide (12). The toxicity evaluation of RIT-treated mice infected intratracheally with C. neoformans showed the absence of acute hematologic and long-term pulmonary toxicity (13). RIT was much better tolerated by the treated mice than Amphoterecin B which is a current standard of care for invasive fungal infections (14). In addition, RIT did not adversely affect bystander mammalian cells such as CHO cells and macrophages, with the latter being able to carry out their functions such as nitric oxide production after RIT exposure (15). As all these observations have been made for systemic administration of the radiolabeled antibodies, the anticipated local application of RIT into the infected joint should be even safer in this regard.”

Journal Requirements

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

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: We have modified the manuscript according to PLOS ONE style.

2. In your Methods section, please give the sources of any bacterial strains used in your study.

Response: We have included the source of bacteria into the Methods

3. 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. We will update your Data Availability statement on your behalf to reflect the information you provide. – Response: We have uploaded the data as a Supporting information file.

4. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ – Response:

ORCID iD has been linked to the manuscript.

5. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. – Response: We are now showing this data in the modified figures.

Attachments
Attachment
Submitted filename: Response to the Reviewers.docx
Revision 2

Reviewer #2:

The authors have addressed the issues raised in the previous review. However, there is little innovation here. It is not clear that there is a specific antibody effect and whatever was observed would be expected. An in vivo study would generate more interest. – Response: We would like to thank the Reviewer for acknowledging that we have addressed the issues in the previous review.

We respectfully disagree about the lack of the innovation. In the revised manuscript we have expanded the sentence in the Discussion stating that: “To the best of our knowledge, this is the first report of RIT treatment of MRSA in particular and of any multidrug resistant bacteria in general in both planktonic and biofilm state”.

We have also added the explanation about some non-specfic killing to the Discussion: “In this regard, the non-specific killing by both radiolabeled bacterium-specific and non-specific

antibodies results from one or combination of two events: 1) in vitro there is always some non-specific killing of cells by highly destructive alpha and beta particles emitted by the radionuclides in a small volume of an assay; 2) WTA-specific 4497 and RSV mAbs are human monoclonal antibodies which, on average, have much higher isoelectric points (IP) than murine antibodies. Antibodies with higher IPs have a tendency to non-specifically bind to the cells, therefore, both radiolabeled 4497 and RSV mAbs demonstrated some non-specific therapeutic effect towards bacterial cells. However, the killing effect of radiolabeled with 213Bi 4497 mAb was higher than that of radiolabeled RSV mAb under examined conditions, indicating that killing of MRSA by 213Bi-4497 mAb was WTA-specific”.

In regard to the animal experiments, they are out of scope of this proof of principle manuscript.

Currently on-going work in animal models on non-invasive nuclear imaging, therapy and safety evaluation will be reported in a follow-up manuscript. We have added a sentence to the conclusions that “the work in the animal models of MRSA infection is currently on-going”.

Attachments
Attachment
Submitted filename: Response to the Reviewers.docx
Decision Letter - Amal Al-Bakri, Editor

Radioimmunotherapy of Methicillin-resistant Staphylococcus aureus in planktonic state and biofilms

PONE-D-19-33702R2

Dear Dr. Dadachova, 

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

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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.

With kind regards,

Amal Al-Bakri

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

**********

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

**********

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

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 #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 #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 #2: While the reviewers did not provide in vivid data, I think the concept is novel enough to warrant publication in the hopes that in vivid data will be forthcoming

**********

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: Yes: Malik E Juweid

Formally Accepted
Acceptance Letter - Amal Al-Bakri, Editor

PONE-D-19-33702R2

Radioimmunotherapy of Methicillin-resistant Staphylococcus aureus in planktonic state and biofilms

Dear Dr. Dadachova:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. 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.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Amal Al-Bakri

Academic Editor

PLOS ONE

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