PNTD-D-24-00646The potential impacts of vector host species fidelity on zoonotic arbovirus transmissionPLOS Neglected Tropical Diseases  Dear Dr. Sulaimon,

Thank you for submitting your manuscript to PLOS Neglected Tropical Diseases. After careful consideration, we feel that it has merit but does not fully meet PLOS Neglected Tropical Diseases'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.

Please submit your revised manuscript within 60 days Feb 11 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosntds@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pntd/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: * A rebuttal letter that responds to each point raised by the editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to any formatting updates and technical items listed in the 'Journal Requirements' section below. * A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. * An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. We look forward to receiving your revised manuscript. Kind regards, Christopher M. BarkerAcademic EditorPLOS Neglected Tropical Diseases Amy GilbertSection EditorPLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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1) Please ensure that the CRediT author contributions listed for every co-author are completed accurately and in full.

At this stage, the following Authors/Authors require contributions: Tijani A Sulaimon, Anthony J Wood, Michael B Bonsall, Michael Boots, and Jennifer S Lord. Please ensure that the full contributions of each author are acknowledged in the "Add/Edit/Remove Authors" section of our submission form.

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Additional Editor Comments: The analyses presented in this manuscript depend on the code developed, and use of a private Github repository is inadequate to ensure availability and reproducibility of the findings. Please include the code as supplementary information with the manuscript or post the code on a public, permanent repository. In addition to the reviewers’ feedback, a PDF is attached with editorial comments.  Reviewers' Comments: Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The objectives of the study are clearly articulated and the hypothesis is clearly tested. The study design is appropriate to test the stated objectives. The research occurred in silico, with adequate sample sizes. Statistical analyses were appropriate. No concerns about ethical or regulatory requirements.

Reviewer #2: -Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

Yes

-Is the study design appropriate to address the stated objectives?

I have a concern with the chosen compartmentalization of susceptible mosquitoes. I'm not sure why there are five categories of mosquitoes in the model - I think its more about tractability, but I'm having a hard time finding the biology in it (especially the infected mosquito fed on dead end host compartment). The nulliparous compartment makes sense, but then to me its not clear how things are moving through the system.

If a mosquito is only infected by the amplifying hosts (pigs), then I think the objective of fidelity would be to model individuals who take a first blood meal on a cow who then take a 1+n blood meal on a pig. The infected compartment would then also represent a mix of individuals who became infected on their first bite + those that eventually become infected on blood meal 1+ n. Once a mosquito is infected (either from the first or second blood meal) it would remain infected, correct?

Delta(nulliparous) = remains as written

Delta(susceptible but blood fed) = (proportion nulliparous fed on an uninfected pig) + (proportion nulliparous/parous fed on any cow) - (proportion susceptible but blood fed who then take a 1+n blood meal on an infected pig)

Delta(infected, blood fed) = (proportion nulliparous fed on an infected pig) + (proportion susceptible but blood fed who then take a 1+n blood meal on an infected pig)

To me, and based on my translation from Figure 1 (which clearly displays the individual-level process of blood feeding) to equation 3 (which presents a population level process), fidelity only weighs that 1+n blood meal.

Please clarify these concerns.

-Is the population clearly described and appropriate for the hypothesis being tested?

Yes

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

NA

-Were correct statistical analysis used to support conclusions?

NA

-Are there concerns about ethical or regulatory requirements being met?

No

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The analysis presented matches the analysis plan. The results are presented clearly, although in the general comments I have a minor suggestion to make them clearer. Figures and tables are generally clear, although I have one comment on a supplemental figure (see general comments section).

Reviewer #2: -Does the analysis presented match the analysis plan?

Yes

-Are the results clearly and completely presented?

Yes

-Are the figures (Tables, Images) of sufficient quality for clarity?

Yes

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The conclusions are supported by the data presented. The limitations are mostly described. The authors clearly explain how the simulation can be helpful to advance our understanding of vector-borne diseases.

Reviewer #2: -Are the conclusions supported by the data presented?

Yes

-Are the limitations of analysis clearly described?

Yes though the model also shows vector abundance can overcome limitations of preference/fidelity though this is not mentioned in the discussion or results.

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

Yes

-Is public health relevance addressed?

Yes

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: See summary and General Comments below.

Reviewer #2: I found myself conflating definitions of preference, fidelity, (vector) memory, and imprinting. Preference is rightfully the genetic basis of host choice (the probability the mosquito a priori chooses a host). Fidelity - defined as imprinting, makes sense too bu that definition is presented too late in the manuscript. The distinction that fidelity only comes into play AFTER initial blood feeding could be a lot clearer in the report as well.

The introduction is a bit bumpy - meaning the flow of ideas sometimes is not as concise as it could be. For instance, over twenty lines are given to describing a single, prior published paper? Also, some paragraphs are only 1 - 2 sentences.

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The authors present a mathematical model to explore the role of host fidelity in mosquito-borne disease transmission, using Japanese encephalitis virus as an example. The article is well written. The conclusions follow logically from the model.

I have only minor comments:

The manuscript side-steps another potential mechanism for increasing amplification where amplifying hosts are less common and less preferred: local spatial heterogeneity. Even if pigs are outnumbered 140:1 at the regional scale, pigs may be locally concentrated and might outnumber cattle at the scale of an individual farm

Range for gamma in Table 3 is incorrect – should be fractions as for the other parameters.

The citation for the biting rate estimate was for Cx. quinquefasciatus. Is there a reason this species was chosen? I do not have access to the paper, to see if it provides biting rates for additional species. Taking a blood meal every 3 days strikes me as a fast turn-around for Culex, although biting rate is influenced by temperature. Not a major concern though, given the lack of sensitivity to biting rate in the sensitivity analysis.

Figure 4: A supplemental table with the total numbers infected would be helpful (or the numbers placed in the whitespace in the graph). I couldn’t quite tell which resulted in more infected overall – a longer lower peak or the sharper higher peaks.

Figure S2: Is the y-axis label correct? Isn’t this something to do with the likelihood of a given fidelity value? The methods used to calculate the fidelity estimates also come across as somewhat opaque to me – I’m not following the methods used here, except in the broadest sense.

Reviewer #2: In general, the manuscript investigates how blood meal imprinting (i.e., learned blood feeding) alters JEV transmission dynamics and then estimates vectoring potential of three important vector species. This is an interesting topic and relevant to the field of JEV and other VBD systems/models.

My primary scientific concern is that the fidelity-based ODEs, to me, don't match the biologically relevant stages of vectors - fidelity as presented in the manuscript should be more about tracking the development of infections in those species that initially blood fed on a dead end host, and simpler Susceptible/Infected classes of vectors may be just as efficient (and realistic) as those developed by the authors. My primary editorial concern is a stronger, clearer definition of fidelity is needed sooner in the manuscript and language needs to be more consistent between preference, fidelity, and imprinting.

A few other minor and specific comments:

Line 37: only anopheles (the genus) is listed (?)

Lines 174 - 183 should come sooner in the methods

Table 3: Mwandawiro 1999/2000 are foundational papers for this model. What were their estimates of fidelity - i.e., whats a realistic range of fidelity?

Lines 262 - 268: no citations?

Discussion of cattle and malaria extensions - I think an important caveat is that feeding on cattle (in amplification outcomes) generates increased vector abundance such that while the fraction of the infected population is small, the overall population is enormous!. In this instance, fidelity would lead to perhaps non-linear increases in vector abundance (and a secondary outcome would be nonlinear changes in transmission)

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Reviewer #1: No

Reviewer #2: No

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Attachments

Attachment

Submitted filename: PNTD-D-24-00646 editor(1).pdf

Dear Sulaimon,

We are pleased to inform you that your manuscript 'The potential impacts of vector host species fidelity on zoonotic arbovirus transmission' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

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 Neglected Tropical Diseases.

Best regards,

Paul O. Mireji, PhD

Section Editor

PLOS Neglected Tropical Diseases

Paul Mireji

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The objectives are clear, the study design is appropriate, the population is clearly defined, the sample size is adequate, statistical analyses were appropriate, no ethical concerns on my side.

Reviewer #2: (No Response)

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The analysis presented matches the analysis plan, the results are clear and completely presented, the figures are sufficiently clear.

Reviewer #2: (No Response)

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The conclusions are supported by the data presented, the limitations of the analysis are adequately described, the authors describe the relevance of the study.

Reviewer #2: (No Response)

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: I believe the results are well presented and sufficient.

Reviewer #2: (No Response)

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: All my previous comments were addressed and I have no further comments.

Reviewer #2: I think the edits/modifications are appropriate and help readers follow the flow of the models.

A small editorial suggestion is the provided definitions of preference, fidelity, and choice could be placed even earlier in the manuscript - line 52 introduces memory/fidelity with no clear meaning of these terms. I think lines 54-61 appropriately introduce the concepts of memory but still lack a definition to guide a reader. The PLOS NTD audience is familiar with choice and preference as concepts AND parameters but not necessarily with fidelity, so a clear conceptual explanation of fidelity needs to come before methods since it is central to the objective of the manuscript.

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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: No

Reviewer #2: No