Dear Professor Smith,

Thank you very much for submitting your manuscript "Spatial Dynamics of Malaria Transmission" 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. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

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

[1] A letter containing a detailed list of your responses to all 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.

Thank you again for your submission to our journal. 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,

James M McCaw, PhD

Academic Editor

PLOS Computational Biology

James O'Dwyer

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: This paper presents a general mathematical framework for modelling the spatial dynamics of the transmission of falciparum malaria. The paper is incredibly well written and presents the modular framework very clearly. It will be very helpful for anyone new to the malaria modelling field but also for those already in the research area wanting to expand to spatial models. I have only a couple of comments:

• It would be good to have a sense of any other frameworks that are available and how they might compare, e.g. from Institute for Disease Modelling or other groups?

• Since the framework solves systems of ODEs, it would be helpful to have a sense of the contexts that this framework could apply to. Eg control, elimination, both?

Reviewer #2: This is a very well written discription of detailed, yet adaptable / scaleable framework for a spatial malaria model.

The framework is well constructed and appears to be both logically and mathematically consistent and appropriate. I particularly like the very clear and logical separation of structural and dynamic components of the model as well as the explicit spcification of spatial matrices. Another very nice and useful approach the use to the reproductive number to assess the importance of different model components to transmission and their importance for predicting impact of different control measure tragetting individual components.

The challenges with this very nice conceptual framework is that although an implementation in R code, the presentation feel largely a theoretical framework rather than demonstrating its actual implementation. Some of the model component - in particular the spatial structures and the detailed vector components are very detailed and require complex parameterisation (with most parameters being vectors or matrices). Doing this in practice. Defining these parameters will require a lot of data (which may not be available for many other settings) and very extensive model fitting to work in any actual implementation of the model framework. It would be great to see more details on the authors implemented their framework for bioko but I assume that will happen in one or several follow-up publication.

Another minor concern is that in the presented implementation of epidemiologica / within host model is simple. This is sufficient to demonstrate how the differnt components of the framework fit together and interact but - as the authors point out - may have to be substantially more complex for addressing specific public health question.

Lastly, I do have some concerns in regards to who may actually be able to use the R code that is provided. It is very well written, beautiful code. However, it seems to fall a bit in between potential two main user classes. Given that for any extensions/ adaptations specific ODEs need to be specified and programmed, users that are not well familiar with writting and programming ODEs may struggle to adapt the code to their setting and problem. On the other hand highly proficient ODE programmers might find it it (almost) as fast to just program their model from scratch.

However, none of these minor concerns distract from the high quality of the manuscript.

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes: Jennifer Flegg

Reviewer #2: No

Figure Files:

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References:

Review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Dear Professor Smith,

Thank you very much for resubmitting your manuscript "Spatial Dynamics of Malaria Transmission" for consideration at PLOS Computational Biology.

Having reviewed your response to the reviewers, and noted the minor changes made, before accepting the manuscript I have one final request: Please include in the main text a brief discussion on the second point raised by Reviewer 1 ("Since the framework solves systems of ODEs, it would be helpful to have a sense of the contexts that this framework could apply to. Eg control, elimination, both?"). Your response letter covers the advantages and "obvious disadvantage(s)" (lack of stochasticity so issue in apply to small population sizes and/or when disease is near extinction) but this needs to be clearly and explicitly described in the manuscript itself.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

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

[1] A letter containing a detailed list of your responses to all 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.

Thank you again for your submission to our journal. 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,

James M McCaw, PhD

Academic Editor

PLOS Computational Biology

James O'Dwyer

Section Editor

PLOS Computational Biology

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

A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

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

References:

Review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Dear Professor Smith,

We are pleased to inform you that your manuscript 'Spatial Dynamics of Malaria Transmission' 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,

James M McCaw, PhD

Academic Editor

PLOS Computational Biology

James O'Dwyer

Section Editor

PLOS Computational Biology

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