PPATHOGENS-D-25-02442

Seasonal forcing and waning immunity drive the sub-annual periodicity of the COVID-19 epidemic

PLOS Pathogens

Dear Dr. Rubin,

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

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We look forward to receiving your revised manuscript.

Kind regards,

Adi Stern

Academic Editor

PLOS Pathogens

Alexander Gorbalenya

Section Editor

PLOS Pathogens Sumita Bhaduri-McIntosh

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0003-2946-9497 Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

Additional Editor Comments:

Dear authors,

I have seen and read your interesting paper together with reviews that were transferred from the journal Science.

I tend to agree very much with the reviewers, that the paper addresses an important and interesting question. However, there are problems both with the modeling and with the data at hand and the ability to answer the opening questions. Could you please revise the paper and add a point-by-point response to the reviewer's comments (some of which seem to have already been addressed).

Additionally, please revisit the text and distinguish the disease (COVID-19) and the virus (SARS-CoV-2). In this regard, statistic inflation of COVID-19 cases by asymptomatic cases of SARS-CoV-2 infection may warrant consideration. You may want to consult https://doi.org/10.1371/journal.pbio.3002130 for the matter. for the matter.

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Attachments

Attachment

Submitted filename: ReviewsFromScienceMagazine.pdf

PPATHOGENS-D-25-02442R1

Seasonal forcing and waning immunity drive the sub-annual periodicity of the COVID-19 epidemic

PLOS Pathogens

Dear Dr. Rubin,

Thank you for submitting your manuscript to PLOS Pathogens. After careful consideration, we feel that it has merit but does not fully meet PLOS Pathogens'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 by Apr 04 2026 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 plospathogens@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/ppathogens/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

* A 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,

Adi Stern

Academic Editor

PLOS Pathogens

Alexander Gorbalenya

Section Editor

PLOS Pathogens

Sumita Bhaduri-McIntosh

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0003-2946-9497

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

Additional Editor Comments:

This is a much improved manuscript with valuable insights, and the reviewer suggest some very minor edits here.

Consider replacing "SARS-CoV-2 virus" with "SARS-CoV-2" to avoid redundancy, since "V" stands for "virus"

Reviewers' Comments:

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: This is a much-improved manuscript that convincingly argues that the observed patterns in COVID cases across the US between 2020 and 2023 stem from a combination of seasonal forcing and rapid waning of immunity. The additional Discussion text on VoCs and how their emergence and circulation patterns interplay or can be interpreted in the context of this model is helpful.

**********

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.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: Model equations (1-5) in the Results section duplicate model equations (9-12) in the Methods section. I suggest removing equations (1-5) and keeping equations (9-12) in the Methods section since the model provides a Method for analysis.

It would be helpful to get an idea of what the annual attack rates are of the subset of simulations that reproduce characteristics of the observed seasonal patterns (e.g., attack rates of simulations using immunity waning functions shown in Fig S7). Are these annual attack rates reasonable/supported by empirical data, e.g., serological surveys/longitudinal studies of antibody dynamics? With such rapid rates of waning and the dynamics shown in the first row of Fig S7, my guess would be that annual attack rates would be relatively high? (Greater than the 10-20% estimated for flu.)

At the state level, how were the min and max temperatures calculated? Were measurements from the most highly populated county used or data somehow averaged across counties (weighted by population size)? Lines 450-452 do not provide sufficient information on this.

**********

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: Abstract: please mention time period of COVID studied (the author summary indicates ‘during the pandemic period’ but this is not mentioned in the abstract)

Line 14 (“In the case of the COVID-19 epidemic…”): please include some citations here. If a reader 10 years down the line is reading this paper, these waves might not be in their working memory

Line 47: 7-day rolling average: this is sensible but perhaps include an explanation of why you chose 7-days for the rolling average. (Are there day-of-the-week reporting trends?)

End of Intro: county-level analysis is indicated but large portion of the Results are at the state level. This seems inconsistent. I suggest adding text to the end of the intro section indicating that both state and county level analyses will be performed.

Fig 2B: The linear regression does not seem to capture the data points very well. Consider (only for this panel) to also show a spline fit or logistic-like curve to highlight that there might be a threshold effect?

**********

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Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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While revising your submission, we strongly recommend that you use PLOS’s NAAS tool (https://ngplosjournals.pagemajik.ai/artanalysis) to test your figure files. NAAS can convert your figure files to the TIFF file type and meet basic requirements (such as print size, resolution), or provide you with a report on issues that do not meet our requirements and that NAAS cannot fix.

After uploading your figures to PLOS’s NAAS tool - https://ngplosjournals.pagemajik.ai/artanalysis, NAAS will process the files provided and display the results in the "Uploaded Files" section of the page as the processing is complete. If the uploaded figures meet our requirements (or NAAS is able to fix the files to meet our requirements), the figure will be marked as "fixed" above. If NAAS is unable to fix the files, a red "failed" label will appear above. When NAAS has confirmed that the figure files meet our requirements, please download the file via the download option, and include these NAAS processed figure files when submitting your revised manuscript.

Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit 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 Mr. Rubin,

We are pleased to inform you that your manuscript 'Seasonal forcing and waning immunity drive the sub-annual periodicity of the COVID-19 epidemic' 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.

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

Best regards,

Adi Stern

Academic Editor

PLOS Pathogens

Alexander Gorbalenya

Section Editor

PLOS Pathogens

Sumita Bhaduri-McIntosh

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0003-2946-9497

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

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

All comments have been addressed, looking forward to seeing this out!

Reviewer Comments (if any, and for reference):