Dear Dr Corder,

Thank you very much for submitting your manuscript 'Modelling the epidemiology of residual Plasmodium vivax malaria in a heterogeneous host population: a case study in the Amazon Basin' for review by PLOS Computational Biology. Your manuscript has been fully evaluated by the PLOS Computational Biology editorial team and in this case also by independent peer reviewers. The reviewers appreciated the attention to an important problem, but raised some substantial concerns about the manuscript as it currently stands. While your manuscript cannot be accepted in its present form, we are willing to consider a revised version in which the issues raised by the reviewers have been adequately addressed. We cannot, of course, promise publication at that time.

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.

Your revisions should address the specific points made by each reviewer. Please return the revised version within the next 60 days. If you anticipate any delay in its return, we ask that you let us know the expected resubmission date by email at ploscompbiol@plos.org. Revised manuscripts received beyond 60 days may require evaluation and peer review similar to that applied to newly submitted manuscripts.

In addition, when you are ready to resubmit, please be prepared to provide the following:

(1) A detailed list of your responses to the review comments and the changes you have made in the manuscript. We require a file of this nature before your manuscript is passed back to the editors.

(2) A copy of your manuscript with the changes highlighted (encouraged). We encourage authors, if possible to show clearly where changes have been made to their manuscript e.g. by highlighting text.

(3) A striking still image to accompany your article (optional). If the image is judged to be suitable by the editors, it may be featured on our website and might be chosen as the issue image for that month. These square, high-quality images should be accompanied by a short caption. Please note as well that there should be no copyright restrictions on the use of the image, so that it can be published under the Open-Access license and be subject only to appropriate attribution.

Before you resubmit your manuscript, please consult our Submission Checklist to ensure your manuscript is formatted correctly for PLOS Computational Biology: http://www.ploscompbiol.org/static/checklist.action. Some key points to remember are:

- Figures uploaded separately as TIFF or EPS files (if you wish, your figures may remain in your main manuscript file in addition).

- Supporting Information uploaded as separate files, titled Dataset, Figure, Table, Text, Protocol, Audio, or Video.

- Funding information in the 'Financial Disclosure' box in the online system.

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.

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. For instructions see here. 

We are sorry that we cannot be more positive about your manuscript at this stage, but if you have any concerns or questions, please do not hesitate to contact us.

Sincerely,

Jennifer A. Flegg

Guest Editor

PLOS Computational Biology

Rob De Boer

Deputy 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:

[LINK]

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: Manuscript Number: PCOMPBIOL-D-19-01472

Thank you for inviting me to review the manuscript titled “Modelling the epidemiology of residual Plasmodium vivax malaria in a heterogeneous host population: a case study in the Amazon Basin ” by Corder et al.

The manuscript used mathematical models to estimate the risk of malaria in the Amazon region while accounting for geographical heterogeneity of the study area.

I have the following comments for major revision.

Major comments:

1. At times the introduction blurred into the results, and the results blurred into the discussion.

For example,

(i) Line 82-89 should be part of the results and not introduction.

(ii) Line 460-464 should be moved to the discussion. The results section should only consist of results. May I suggest you align and insert these sentences into the first paragraph of the discussion.

2. The methodology (mathematical models) is too long consisting about 8 pages of different techniques. Could the authors summarize the techniques into a maximum of 2 pages and moved the detailed mathematical models to supplementary materials.

Minor comments

3. Line 52-53: Insert some references here.

4. The authors mentioned in line 52-53 that varying malaria risks have been observed in several towns and cities in Africa countries. However, the example provided was in the city of Brazzaville (Not an African city/country).

5. Line 54-58: Insert references here.

6. Line 77-78: It will be nice to have a sentence describing what residual transmission is.

7. Line 216: …the antimalaria drugs used for radical cure of vivax malaria in Brazil. Provide a reference for this statement.

8. Line 377. Here and throughout the manuscript insert “95% CI” in front of the 95% Credible Interval (CI). Eg. 0.0883 [95% CI: 0.0801-0.1189]

9. Line 506: “…the model predicts that as much as 25 past malaria…” By 25 in this statement, are they saying 25% of past malaria?

Reviewer #2: This manuscript presents fine work. It is based on very good data: a town in Brazil with high malaria incidence, monitored during one year, person by person. This is a piece of exceptional data.

The work adresses the question of risk heterogeneity, an important one. And it proposes a mathematical model that is shown to fit very well the data.

So far, so good, but I would like to raise some points.

1- I don’t really get the point why the two risk classes do not interact. Are the people in those two risk classes somehow geographically separated? Because, if they are mixed, wouldn’t it be the case of a HR person being a potential spreader in the LR population. Please clarify the assumptions of the model at this point.

2-Could you make explicit the parameters that are being fitted. I understand that including age classes is realistic, but also introduces new parameters. Expression (1), for instance has two parameters. Lambda zero is not a problem, but the parameter “k”in Eq.(1) seems arbitrary. Is it a free parameter to be fitted?

3- The model predicts that “As much as 25 past malaria attacks are required in order to reduce by half the risk of a clinical malaria attack”. Is this reasonable? Any other studies show this ? It would be nice to see a discussion on this point.

As I mentioned above, this is a good work, and deserves to be published in a good journal. But it would be interesting to have a more thorough discussion on the model assumptions and parameter “proliferation” .

**********

Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: Yes

Reviewer #2: 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: No

Reviewer #2: No

Dear Dr Corder,

Thank you very much for submitting your manuscript, 'Modelling the epidemiology of residual Plasmodium vivax malaria in a heterogeneous host population: a case study in the Amazon Basin', to PLOS Computational Biology. As with all papers submitted to the journal, yours was fully evaluated by the PLOS Computational Biology editorial team, and in this case, by independent peer reviewers. The reviewers appreciated the attention to an important topic but identified some aspects of the manuscript that should be improved.

We would therefore like to ask you to modify the manuscript according to the review recommendations before we can consider your manuscript for acceptance. Your revisions should address the specific points made by each reviewer and we encourage you to respond to particular issues 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.raised.

In addition, when you are ready to resubmit, please be prepared to provide the following:

(1) A detailed list of your responses to the review comments and the changes you have made in the manuscript. We require a file of this nature before your manuscript is passed back to the editors.

(2) A copy of your manuscript with the changes highlighted (encouraged). We encourage authors, if possible to show clearly where changes have been made to their manuscript e.g. by highlighting text.

(3) A striking still image to accompany your article (optional). If the image is judged to be suitable by the editors, it may be featured on our website and might be chosen as the issue image for that month. These square, high-quality images should be accompanied by a short caption. Please note as well that there should be no copyright restrictions on the use of the image, so that it can be published under the Open-Access license and be subject only to appropriate attribution.

Before you resubmit your manuscript, please consult our Submission Checklist to ensure your manuscript is formatted correctly for PLOS Computational Biology: http://www.ploscompbiol.org/static/checklist.action. Some key points to remember are:

- Figures uploaded separately as TIFF or EPS files (if you wish, your figures may remain in your main manuscript file in addition).

- Supporting Information uploaded as separate files, titled 'Dataset', 'Figure', 'Table', 'Text', 'Protocol', 'Audio', or 'Video'.

- Funding information in the 'Financial Disclosure' box in the online system.

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.

We hope to receive your revised manuscript within the next 30 days. If you anticipate any delay in its return, we ask that you let us know the expected resubmission date by email at ploscompbiol@plos.org.

If you have any questions or concerns while you make these revisions, please let us know.

Sincerely,

Jennifer A. Flegg

Guest Editor

PLOS Computational Biology

Rob De Boer

Deputy 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:

[LINK]

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #2: As mentioned in my first review, I consider that this manuscript presents fine work. My questions have been partially answered.

Regarding the following statement of the authors:

"Indeed, the model predicts that as much as 25 past clinical malaria attacks are required in order to reduce by half the risk of a clinical malaria attack. In holoendemic settings, children are typically continuously infected during the transmission season, with frequent superinfection and overlapping clinical malaria episodes during their first years of life. "

Could the authors provide a reference. This is a strong and quantitative (25 cases) statement and it just floats around.

A reference for "In other words, HR individuals in our Amazonian study population are nearly as

545 exposed to malaria as the average child living in rural Africa." would also be welcome.

These are minor points that can be easily assessed.

------------

As an aside: moving all equations and mathematical details to S1 resulted in a poorer text. Equations speak by themselves and are much clearer than a description in words. Anyhow, this was done because the other reviewer ask it, so I will not suggest to go back to the previous version.

**********

Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #2: 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 #2: No

Dear Mr. Corder,

We are pleased to inform you that your manuscript 'Modelling the epidemiology of residual Plasmodium vivax malaria in a heterogeneous host population: a case study in the Amazon Basin' 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 within two working days 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,

Jennifer A. Flegg

Guest Editor

PLOS Computational Biology

Rob De Boer

Deputy 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 #2: I have no further comments, and I think that now the paper is ready for publication.

**********

Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #2: 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 #2: No