PONE-D-25-23454THE STRUCTURE OF THE PROTEINS OF CAMP HILL VIRUSPLOS ONE

Dear Dr. Thomas,

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 risk of henipavirus outbreaks is increasing due to human activities such as deforestation, which forces greater interaction between humans and bats, the primary zoonotic reservoir hosts.": there are no references to support this statement. More references should be cited, with this one (PMID: 38042947) as an example (citing is optional).

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PLOS ONE

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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: Partly

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:  Reviewer:

Comments to the Author

In the current manuscript, Thomas et al, presents a structural and immunoinformatic analysis of the proteins of Camp Hill virus (CHV), a newly identified henipavirus in North America. The subject is timely and relevant, given the zoonotic potential of henipaviruses. The integration of structural prediction tools and epitope mapping offers a valuable contribution to early vaccine design efforts. However, the manuscript requires substantial revisions in terms of scientific rigor, clarity, and novelty justification.

Major comments :-

1. While the identification of CHV is interesting, the manuscript fails to clearly define the novel scientific insights derived from this study. It is largely descriptive, with little comparative or functional interpretation

2. The structural analyses and epitope mapping are standard computational exercises. Without experimental validation, it is difficult to judge the translational potential

3. The study heavily depends on AlphaFold and I-TASSER predictions. Confidence metrics (e.g., low C-scores) suggest many models are unreliable

4. Epitope predictions (IEDB) are speculative without immunological assays or population coverage assessment.

5. No investigation is made into how the predicted epitopes might be processed or presented in the context of actual MHC molecules or host immune systems.

6. The manuscript has several grammatical errors, awkward phrasing (e.g., “CHV is not infected in humans”), and repetitive expressions (e.g., “The predicted structure provides insights…” is repeated verbatim)

7. Figures and tables are cited inconsistently and sometimes lack proper legends or interpretation.

8. The discussion repeats large portions of the introduction

9. A critical appraisal of results is missing, such as why certain proteins share higher identity with other henipaviruses, and implications for cross-reactivity or zoonotic potential

Minor comments:-

1. Table 3 should include a clearer explanation of how similarity scores were calculated (e.g., pairwise BLAST or Clustal Omega?)

2. Figures 1–8: Consider integrating the B-factor and solvent accessibility plots into a single composite figure per protein

3. The Data Availability Statement should specify if model PDB files will be made public

4. Abbreviations should be defined consistently on first use (e.g., RMSD, TM-score). Consider preparing an abbreviation table.

Reviewer #2:  Nipah virus has the potential for recurrent outbreaks and a high fatality rate. Currently, there are no effective preventive vaccines or specific antiviral drugs available, and treatment primarily relies on systemic symptomatic supportive therapy. Nipah virus has been included by the World Health Organization in its Priority Pathogens Blueprint List, necessitating monitoring and preparedness measures to prevent a pandemic.

The paper presents structural analysis and functional predictions of Camp Hill virus (CHV), a newly discovered Henipavirus, first reported in North America. A systematic structural analysis was conducted on the viral attachment glycoprotein, fusion protein, X protein, C protein, matrix protein, nucleocapsid protein, phosphoprotein, and RNA polymerase, focusing on the presence and location of viral proteins, domains and spatial conformation of receptor interactions and immune recognition, B-cell and T-cell epitopes, structural feature analysis, and recognition regions of antibody and immune effector.

The paper is logically clear, methodologically systematic, and conclusive. It provides structural biology reference data for understanding the possibility of human infection with CHV, comprehending its potential transmission routes and those of other shrew-borne viruses, formulating corresponding prevention strategies including vaccines, and identifying potential targets for drug development.

Although a study does not need to be fully reflected in one single paper, virus structure prediction articles, such as this paper, which analyzes from a bioinformatics perspective, do not have any major flaws. However, from a virology perspective, it is still hoped that the corresponding prediction conclusions can be verified in terms of protein function at levels of the cellular or corresponding model animals especially.

In addition, please ensure consistency in the number of decimal places retained for the percentages in Table 3.

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Reviewer #1: Yes:  Pratibha Gaur

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Reviewers comments.doc

THE STRUCTURE OF THE PROTEINS OF CAMP HILL VIRUS

PONE-D-25-23454R1

Dear Dr. Thomas,

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,

Benjamin M. Liu, MBBS, PhD, D(ABMM), MB(ASCP)

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 #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: NA

They have presented and answered the questions asked by reviewer.

Reviewer: 4

Comments to the Author

In the current manuscript, Thomas et al, presents a structural and immunoinformatic analysis of the proteins of Camp Hill virus (CHV), a newly identified henipavirus in North America. The subject is timely and relevant, given the zoonotic potential of henipaviruses. The integration of structural prediction tools and epitope mapping offers a valuable contribution to early vaccine design efforts. However, the manuscript requires substantial revisions in terms of scientific rigor, clarity, and novelty justification.

Major comments :-

1. While the identification of CHV is interesting, the manuscript fails to clearly define the novel scientific insights derived from this study. It is largely descriptive, with little comparative or functional interpretation

2. The structural analyses and epitope mapping are standard computational exercises. Without experimental validation, it is difficult to judge the translational potential

3. The study heavily depends on AlphaFold and I-TASSER predictions. Confidence metrics (e.g., low C-scores) suggest many models are unreliable

4. Epitope predictions (IEDB) are speculative without immunological assays or population coverage assessment.

5. No investigation is made into how the predicted epitopes might be processed or presented in the context of actual MHC molecules or host immune systems.

6. The manuscript has several grammatical errors, awkward phrasing (e.g., “CHV is not infected in humans”), and repetitive expressions (e.g., “The predicted structure provides insights…” is repeated verbatim)

7. Figures and tables are cited inconsistently and sometimes lack proper legends or interpretation.

8. The discussion repeats large portions of the introduction

9. A critical appraisal of results is missing, such as why certain proteins share higher identity with other henipaviruses, and implications for cross-reactivity or zoonotic potential

Minor comments:-

1. Table 3 should include a clearer explanation of how similarity scores were calculated (e.g., pairwise BLAST or Clustal Omega?)

2. Figures 1–8: Consider integrating the B-factor and solvent accessibility plots into a single composite figure per protein

3. The Data Availability Statement should specify if model PDB files will be made public

4. Abbreviations should be defined consistently on first use (e.g., RMSD, TM-score). Consider preparing an abbreviation table.

Reviewer #2: Thanks the authors for their prompt response to the review comments.

The limitations of the experimental scope and the detailed presentation of accurate data reflect the rigorous logic of the paper and the authors' comprehensive understanding of the data.

The analysis of the structure of the newly discovered Henipavirus in North America presented in this paper may promote research on the pathogenicity, immunogenicity, and vaccine preparation of the virus for prevention and treatment.

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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: No

Reviewer #2: No

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