Dear Mr. Paredes,

Thank you very much for submitting your manuscript "Local-Scale phylodynamics reveal differential community impact of SARS-CoV-2 in metropolitan US county" for consideration at PLOS Pathogens. 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.

Both reviewers agree this is an excellent high quality paper and have a series of important small suggestions. Of note esp. is comment 6 of reviewer 2 - it is important to contextualize this paper for broad readership, and give examples of how this study can inform us beyond the particular case of north/south king county (which may very well reflect similarity to many other large cities?).

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,

Adi Stern

Academic Editor

PLOS Pathogens

Alexander Gorbalenya

Section Editor

PLOS Pathogens

Kasturi Haldar

Editor-in-Chief

PLOS Pathogens

​orcid.org/0000-0001-5065-158X

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

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

Both reviewers agree this is an excellent high quality paper and have a series of important small suggestions. Of note esp. is comment 6 of reviewer 2 - it is important to contextualize this paper for broad readership, and give examples of how this study can inform us beyond the particular case of north/south king county (which may very well reflect similarity to many other large cities?).

Reviewer Comments (if any, and for reference):

Reviewer's Responses to Questions

Part I - Summary

Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship.

Reviewer #1: The study investigates the transmission dynamics of SARS-CoV-2 at a local level in King County, Washington, utilizing genomic, epidemiological, and mobility data from February 2020 to March 2022. The authors employ an advanced analysis method to uncover significant disparities in transmission patterns between North and South King County following the implementation of stay-at-home orders. Notably, South King County experienced higher reported cases, hospitalizations, and sustained local transmission compared to North King County, where new cases are primarily influenced by importation from outside the county. These disparities are attributed to diverse mobility and socioeconomic challenges faced by residents of South King County, emphasizing the importance of considering local conditions in pandemic management. The study is exceptionally well-written report, the results are well presented, and includes an impressive phylodynamic analysis pipeline. A few remarks are listed below for consideration.

Reviewer #2: This study uses 11,737 SARS-Cov-2 sequences sampled from January 2020 – March 2022 from people living in King County, Washington (which includes the city of Seattle) to study patterns of virus transmission, including community spread versus the role of outside introductions in driving the epidemic. These approaches have been successfully used around the world to evaluate the impact of non-pharmaceutical interventions on controlling virus transmission.

**********

Part II – Major Issues: Key Experiments Required for Acceptance

Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions.

Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject".

Reviewer #1: - In the Methods section, please provide a comprehensive explanation of the selection process for contextual sequences, as identifying local clusters through phylogenetic inference is a critical aspect of this study.

Reviewer #2: 1. This paper discusses the role of outside introductions. Did North King county and South King county appear to have the same geographical sources for these introductions? Did the geographical source of outside introductions shift over the course of the pandemic?

2. One question during the pandemic was why alpha did not take off in the US the way it did in the UK where it emerged. When was the variant introduced into King County? Did you observe lots of introductions but not much community transmission? Any idea why?

3. Is there any parameter that is a good predictor of whether a transmission chain persists for a long period? Seasonality? Population immunity? Location of origin? Timing related to non-pharmaceutical interventions? Or does it appear to be stochastic?

**********

Part III – Minor Issues: Editorial and Data Presentation Modifications

Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity.

Reviewer #1: - The statement “Figure 2c shows all clusters greater than size five with respective posterior support for inferred ancestral states.” is redutant as it repeats the earlier statement.

- Please label control measures in Fig. 1 C and D, and Fig. 5A

- Typo? mzy -> myz

- In the sentence “21,976 genome sequences from around the world downloaded from GISAID”, the contextual sequences for Omicron, Delta, Alpha and other lineages exceed this total number.

Reviewer #2: 1. What is most interesting about this study is the comparison of transmission dynamics between North King County and South King County and how their differ. (North is more driven by outside introductions, whereas South has more community transmission). But while the authors may be familiar with the differing demographics of these two regions, the reader has to make it all the way to Figure 6 (page 22) to get a picture of how these two regions differ socioeconomically, in % essential workers, etc. It would be helpful to move Figure 6 to the beginning of the paper and include some text in the introduction. Can the authors provide any clarity on why there seems to be such a stark socioeconomic line in the middle of King County? Why do adjacent zip codes in the middle of the county differ so much in socioeconomic measures? Could you also provide a map with population density in Figure 6? Possibly vaccination rates?

2. This study examines transmission in the context of non-pharmaceutical interventions like stay at home orders and closing bars. What about closing schools?

3. I could not find any MCC trees or ML trees in the GitHub repository. Figure 2 is missing background data so the King County data is more visible but there are some surprisingly large King County clusters, given how fluidly SARS-CoV-2 mixes within and between states. Are these monophyletic? And the very long branches (appears to be delta? some labeling of the different variants in the tree would help), are these chronically infected people? One of the branches spans >6 months. What % of transmission chains (maybe with at least 10 sequences) are only found in one region (north or south) versus both?

4. In your models, did you use the same parameters throughout, or change them as new variants arrived?

5. It would be helpful in all the figures to label the variants in the different waves (e.g., Fig 3). Most readers probably know them, but when people this read this paper 5-10 years from now they may forget.

6. Could your discussion include some more concrete examples of how this kind of molecular epidemiology could, in retrospect, change how policy makers acted during the pandemic? Based on these findings, could they have targeted interventions differently or more strategically? Is one takeaway that a region's COVID control is only as good as its weakest link, because any pocket where cases are high will quickly seed other areas? What is your main takeaway?

**********

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

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 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:

Please 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 Mr. Paredes,

We are pleased to inform you that your manuscript 'Local-Scale phylodynamics reveal differential community impact of SARS-CoV-2 in metropolitan US county' has been provisionally accepted for publication in PLOS Pathogens.

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 Pathogens.

Best regards,

Sonja M. Best, Ph.D.

Section Editor

PLOS Pathogens

Sonja Best

Section Editor

PLOS Pathogens

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

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

Reviewer Comments (if any, and for reference):