Dear Dr. Pandey,

Thank you very much for submitting your manuscript "Wildlife vaccination strategies for eliminating bovine tuberculosis at the wildlife-livestock interface" for consideration at PLOS Computational Biology.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the 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.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Yamir Moreno

Academic Editor

PLOS Computational Biology

Virginia Pitzer

Section Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: Pandey et al. have used a modeling approach to assess vaccination strategies for eliminating bTB in Michigan white-tailed deer populations. This topic is very relevant to managing a serious wildlife health, public health and economic issue, and timely. I have the following suggestions/comments:

1) bTB surely is an excellent example of a pathogen transmitted at the wildlife-domestic-human interface, but your work exclusively focuses on the wildlife component - you have evaluated strategies for bTB elimination /control in WTD populations, right? I suggest replacing the 'wildlife-livestock interface' in your title to 'white-tailed deer populations'.

2) You compare model results for 4 counties - yet there is no countywise deer population data provided in your paper. How does the N differ between these counties? How does the age composition differ between these counties? Did you use pre-harvest or post-harvest estimates?

3) You have provided parameter values in Table 1. All except the per capita immune waning rate are yearly (annual) rates. How do you account for this in your model?

4) Moreover, you have assumed that per capita harvest rates are same for male and female deer. Could you provide some explanation why you made this assumption when the harvest rates in the real world are clearly different in male and female deer? Do consider that bTB prevalence differs significantly between males (8%) and females (2%) as documented by O'Brien et al 2002. I might have missed any current references on this topic; if so, please include these references.

5) This also brings up the question about the sensitivity analysis - you state that disease prevalence is very sensitive to adult harvest rates. But you make unrealistic assumption about male and female harvest rates. How valid are your conclusions in the context of this assumption?

6) Line 290: Should'nt it be Figure 2?

7) Another critical component missing from your results is the impact of these scenarios on the deer population. For scenarios where harvest and vaccination are combined, could you provide a plot to show the population size of deer? Would help the reader understand the context for these results.

8) Figure 4 would provide critical insights if you extend the x axis (years) to 30? How long does the effect of short term vaccination last?

Reviewer #2: The authors develop an age structured mechanistic model that is fitted on bovine TB surveillance data in white tailed deer in Michigan. They use the models to test effect vaccines (different efficacy and coverage) and deer harvesting on bTB transmission dynamics. The manuscript is beautifully written with a good flow of logic in the introduction, and good explanation of the methods as well as good presentation of the results, and insights drawn from the model. I enjoyed reading it.

I have two main comments for consideration by the authors:

- What is relative contribution of live propagules in the environment to the main outcome modelled (prevalence of bTB)? This number of live propagules in the environment would be expected to be a function of prevalence of bTB in the study population - how is this accounted for in the model?

- The authors rightfully identify sampling bias as a potential limitation to the data used to parametarize the model. I would be keen to see how the model results and interpretation of insights would vary if under ascertainment of the infection rates was incorporated in the model.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —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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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.

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Reviewer #1: Yes: Aniruddha Belsare

Reviewer #2: No

Figure 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. 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.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Dr. Pandey,

Thank you very much for submitting your manuscript "Wildlife vaccination strategies for eliminating bovine tuberculosis in white-tailed deer populations" for consideration at PLOS Computational Biology.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by an independent reviewer. In light of the review (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewer's comments.

Please carefully address the critical comment 1 of the reviewer, which might lead to methodological problems. It may also be helpful to implement a sensitivity analysis testing for the robustness of such an assumption/procedure.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the 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.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Yamir Moreno

Academic Editor

PLOS Computational Biology

Virginia Pitzer

Section Editor

PLOS Computational Biology

***********************

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: Thank you for responding to my comments. I have a few follow-up questions:

1) You state in your response to Comment 2: "In the model, we have assumed constant/continuous harvest of deer throughout the year for simplification. This is further supported by the fact that the USDA removes deer outside of the hunting season." I think this simplistic assumption is problematic. Just considering the harvest data for Alpena County, about 10% of the deer (~2500) are removed (harvested) in the month of November; a total of ~15% (3500) removed during the 4 months of harvest season (Sep-Dec). But, as per your explanation, you are simply dividing the annual harvest rate by 12 to get a monthly harvest rate, so you have 400 deer harvested every month in your model. The sensitivity analysis (Fig. S6) is questionable due to the unrealistic monthly harvest rates. Such simplifying assumptions influence model dynamics and disease dynamics, and in my opinion, negatively impact the applicability and utility of your modeling approach.

2) Do consider converting the finite rates to instantaneous rates instead of just dividing annual rates by 12. See https://influentialpoints.com/Training/finite-and-instantaneous_rates.htm

3) You state that (Line 305) "Prevalence increased in Alpena and Alcona counties over the ten-year period, remained level in Oscoda County and decreased in Montmorency County." Is this based on 'eyeballing' Figure 2, or you used some other statistic? Please provide details here.

4) Similarly, you state (Line 324) "Prevalence was most affected by increase (30%) harvest in Alpena and Alcona counties, whereas very little effect was seen in Montmorency and Oscoda counties." How was this ('most affected', 'little effect') determined? Did you do statistical comparisons? If so, please provide details.

5) It is surprising that you did not discuss in more detail the decreasing prevalence of bTB in Oscoda and Montmorency counties (Figures 3, 4, S16, etc.). As you are using a compartmental model, this means the R0 is less than 1, but in the context of Fig. S17, it might just be due the population threshold size (Nt). This might not reflect real-world process, and majorly affects the relevance of your findings.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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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: Aniruddha Belsare

Figure 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. 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.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Dr. Pandey,

We are pleased to inform you that your manuscript 'Wildlife vaccination strategies for eliminating bovine tuberculosis in white-tailed deer populations' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology. 

Best regards,

Yamir Moreno

Academic Editor

PLOS Computational Biology

Virginia Pitzer

Section Editor

PLOS Computational Biology

***********************************************************

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: Thanks for responding to my comments. Great job!

**********

Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

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: Aniruddha V. Belsare