Association between COVID-19 vaccination, SARS-CoV-2 variants, and post COVID-19 condition: A cross-sectional study

Saif-El-Din El-Akkad; Selena Shao; Karen C. Tran; Hiten Naik; Naveed Janjua; Hind Sbihi; Christopher Carlsten; James A. Russell; Adeera Levin; Alyson W. Wong

doi:10.1371/journal.pone.0336929

Peer Review History

Original SubmissionFebruary 19, 2025
28 May 2025 Decision Letter - Dong Keon Yon, Editor Dear Dr. El-Akkad, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’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 Jul 12 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 plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. 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Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. Please update your Data Availability statement in the submission form accordingly. 3. You have indicated that data is available from [svitlana.franchuk@ors.ubc.ca]. Please can we ask you to provide us with a general contact email address for the data requests, so readers can request access in perpetuity. If a general email is not available please provide a link to a website where readers can obtain access to data. 4. Thank you for stating the following in your manuscript: “AWW received funding from the Canadian Lung Association (CLA) / Canadian Institutes of Health Research (CIHR) Respiratory Health Effects of PCC Grant (Funding reference 181075). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. “ We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “AWW received funding from the Canadian Lung Association (CLA) / Canadian Institutes of Health Research (CIHR) Respiratory Health Effects of PCC Grant (Funding reference 181075). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. Additional Editor Comments (if provided): Thank you for submitting your manuscript. The reviewers and I believe it is of potential value for our readers. However, the reviewers have raised a number of very important issues, and their excellent comments will need to be adequately addressed in a revision before the acceptability of your manuscript for publication in the Journal can be determined. We cannot guarantee that your revised paper will be chosen for publication; this would be solely based on how satisfactorily you have addressed the reviewer comments. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: Not really novel and somewhat outdated now (alpha, gamma, delta variants will not return) - but could be useful data for some cases, e.g. for those making health insurance claims based on complications related to these older variants, or clinicians with such patients trying to understand their spectrum of illness better for management purposes. Reviewer #2: This study provides a clinically relevant investigation into the prevalence and determinants of persistent symptoms among COVID-19 survivors, utilizing a cohort derived from a post-COVID care clinic. By examining associations between vaccination status, SARS-CoV-2 variants, and patient-reported outcome measures (PROMs), the study contributes to the growing literature on post-COVID condition (PCC) and offers important insights into modifiable and non-modifiable factors that may influence long-term recovery. While the authors adjust for several baseline characteristics—including age, sex, and comorbidities—the inclusion of time-dependent covariates would strengthen the analysis. Specifically, stratifying by time since infection or time since last vaccination dose may provide a more nuanced understanding of how temporal dynamics influence post-COVID outcomes. Although the multivariable models account for several relevant factors, residual confounding remains a concern, particularly with respect to COVID-19 illness severity. Disease severity is likely to influence both the risk of developing post-COVID conditions (PCC) and the probability of being referred to a post-COVID recovery clinic. The absence of a non-infected comparison group precludes estimating the absolute risk or excess burden of post-COVID conditions. Without a reference population of individuals who were never infected, it is impossible to determine whether the prevalence of abnormal PROMs (e.g., fatigue, dyspnea, anxiety) is elevated beyond what might be expected in the general population or among those with similar comorbidities but without SARS-CoV-2 exposure. Considering that this is a clinic-based cohort of COVID-19 survivors, there are additional selection biases (referral and survival bias) and generalizability concerns that should be clearly acknowledged in the paper. ****** what does this mean? ). If published, this will include your full peer review and any attached files. 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Revision 1
23 Aug 2025 Author Response August 21st, 2025 We thank the Editors and Reviewers for their review and thoughtful comments. We hope we have addressed this feedback to their satisfaction. Sincerely, Saif El-Akkad, on behalf of the authors Editor’s Comments: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Response: Thank you for sharing the need for additional style and formatting requirements. Using the provided templates the following changes were made: • Title page heading changed to size 18 and bolded. • All author affiliations modified to include department, division, institution, city, province and country. • Only the email for the corresponding author is now provided. • Additional text from the title page (word count, figure/table count, keywords) has been removed from title page. • Abstract has been shortened to 300 words as outlined in submission guidelines. • Changed headings and subheadings to requested format for level 1 and level 2 headings. • Changed “figure” to “fig” as requested throughout the manuscript. • Table 3 and the Figure 3 heading now appear after the paragraph in which they are mentioned. • Table S1 is now referenced in the manuscript body (page 8): “Baseline PROM scores were also collected and the proportion of participants who reported abnormal scores was calculated (Table S1).” • An acknowledgements heading is now provided prior to the references, other headings (list of abbreviations, ethics statement, availability of data and materials, conflicts of interest, funding statements and author contributions) have been moved to their respective sections in the manuscript body or removed if not required by PLOS ONE’s formatting requirements. • Supporting information section now includes both the S1 and S2 tables titles and legends in the requested format. • Figures and supplemental table files have been renamed according to requested format. 2. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Before we proceed with your manuscript, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. Please update your Data Availability statement in the submission form accordingly. Response: According to the University of British Columbia Clinical Research Ethics Board (UBC CREB), we are prohibited from sharing data publicly as there is potentially sensitive information. Data requests may be sent to the UBC CREB at the following address: Room 210, Research Pavilion - 828 West 10th Ave, Vancouver, BC Canada V5Z1M9 The Data Availability statement in the submission form has been updated to the following: “Data requests may be sent to the UBC CREB at the following address: Room 210, Research Pavilion - 828 West 10th Ave, Vancouver, BC Canada V5Z1M9” 3. You have indicated that data is available from [svitlana.franchuk@ors.ubc.ca]. Please can we ask you to provide us with a general contact email address for the data requests, so readers can request access in perpetuity. If a general email is not available, please provide a link to a website where readers can obtain access to data. Response: Data requests may be sent to the UBC CREB at the following address: Room 210, Research Pavilion - 828 West 10th Ave, Vancouver, BC Canada V5Z1M9. A general email is not available, but up-to-date contact information can be found on the UBC CREB website: https://researchethics.ubc.ca/clinical-research-ethics/contact-creb 4. Thank you for stating the following in your manuscript: “AWW received funding from the Canadian Lung Association (CLA) / Canadian Institutes of Health Research (CIHR) Respiratory Health Effects of PCC Grant (Funding reference 181075). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. “ We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “AWW received funding from the Canadian Lung Association (CLA) / Canadian Institutes of Health Research (CIHR) Respiratory Health Effects of PCC Grant (Funding reference 181075). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. Response: The funding statement that was previously provided in the acknowledgements section has been removed. The current funding statement is correct and there are no amendments. 5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. Response: The ethics statement has been removed from the acknowledgement section of the manuscript and is now only mentioned in the methods section as requested. Reviewer: 1 No additional comments to address. Reviewer: 2 R2C1. While the authors adjust for several baseline characteristics—including age, sex, and comorbidities—the inclusion of time-dependent covariates would strengthen the analysis. Specifically, stratifying by time since infection or time since last vaccination dose may provide a more nuanced understanding of how temporal dynamics influence post-COVID outcomes. R2R1: Thank you for this feedback. The median time from infection to completion of PROM questionnaires was approximately 100 days (with interquartile range of 50 days) and similar between the vaccination groups. Time-varying covariates were not included given this relatively short time interval. We have included the median times between infection and questionnaire completion in Table 1. R2C2. Although the multivariable models account for several relevant factors, residual confounding remains a concern, particularly with respect to COVID-19 illness severity. Disease severity is likely to influence both the risk of developing post-COVID conditions (PCC) and the probability of being referred to a post-COVID recovery clinic. R2R2: Patients were stratified into those who were hospitalized and were not hospitalized to address disease severity. We have added the following sentence discussing the impact of disease severity as a potential confounder and how we attempted to minimize its impact on the study (discussion paragraph 5). “We also stratified patients based on whether or not they were hospitalized for COVID-19 as the severity of acute illness may increase the development and severity of PCC (2).” R2C3. The absence of a non-infected comparison group precludes estimating the absolute risk or excess burden of post-COVID conditions. Without a reference population of individuals who were never infected, it is impossible to determine whether the prevalence of abnormal PROMs (e.g., fatigue, dyspnea, anxiety) is elevated beyond what might be expected in the general population or among those with similar comorbidities but without SARS-CoV-2 exposure. R2R3: Thank you for raising this valid concern, we agree that this is a key limitation of the study and have added the text below discussing this limitation and how we attempted to minimize its impact on the study (discussion paragraph 5). “This study is limited by the absence of PROM data prior to COVID-19 infection and lack of a control cohort, which restricts our ability to attribute the presence of abnormal PROMs to PCC. We attempted to focus in on the relationship between COVID-19 infection and abnormal PROMs by adjusting for comorbidities to address the impact that pre-existing conditions and impaired health may have on PROMs.” We have also added additional text that aids in the interpretation of the reported PROM values and their comparison to normative PROM values reported in the general population (Supplemental Table 1). “The full range of scores for the PROMs are as follows, with higher scores reflecting more symptoms: FSS (sum or mean) (0-63 or 0-7), UCSD (0-120), PTSD (0-5), GAD-2 (0-6), PHQ-2 (0-6). To aid in the interpretation of PROM values, the following normal thresholds have been identified in healthy populations: FSS ≤ 3 (11), PTSD < 4 (14,33), GAD-2 < 3 (12,34), PHQ-2 < 3 (13,34).” R2C4. Considering that this is a clinic-based cohort of COVID-19 survivors, there are additional selection biases (referral and survival bias) and generalizability concerns that should be clearly acknowledged in the paper. R2R4: We thank reviewer 2 for raising this suggestion. Concerns around referral bias and the generalizability of this cohort have been addressed in the text below (discussion paragraph 5). “Additionally, while the PCRC cohort represents a large cohort of approximately 3800 patients with COVID-19 who have completed validated questionnaires and physiological testing, there is potential referral bias (e.g., care providers in rural locations may not be aware of the PCRCs and those with mild disease may not be referred to the PCRC). While this population may not be fully generalizable, it does allow us to study patients with sustained and severe PCC who would most likely require and benefit from further investigations and treatment.” Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0336929.r002
9 Sep 2025 Decision Letter - Dong Keon Yon, Editor Dear Dr. El-Akkad, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’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 Oct 24 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 plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. 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We look forward to receiving your revised manuscript. Kind regards, Dong Keon Yon, MD, FACAAI, FAAAAI Academic Editor PLOS ONE Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 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. Additional Editor Comments: # COVID infection. -> SARS-CoV-2 infection # The BCCDC PHL continuously monitors for VOCs, variants of interest (VOIs), and variants under monitoring (VUMs). ?? -> Please describe definition of VOC duration. # COVID-19 infection -> SARS-CoV-2 infection # COVID vaccination -> COVID-19 vaccination # demonstrated -> found [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #2: Yes ****** Reviewer #2: (No Response) ****** 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 ******** [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.] 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. Registration is free. 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 PLOS at figures@plos.org https://doi.org/10.1371/journal.pone.0336929.r003
Revision 2
29 Oct 2025 Author Response October 11th, 2025 We thank the Editors and Reviewers for their review and thoughtful comments. We hope we have addressed this feedback to their satisfaction. Sincerely, Dr. Saif El-Akkad, on behalf of the authors Editor’s Comments: 1. The following additional editor comments were made: a. COVID infection -> SARS-CoV-2 infection b. COVID-19 infection -> SARS-CoV-2 infection c. COVID vaccination -> COVID-19 vaccination d. Demonstrated -> found Response: Thank you for sharing the need for additional style and formatting requirements. The following changes were made: • COVID infection has been changed to SARS-CoV-2 infection. • COVID-19 infection has been changed to SARS-CoV-2 infection. • COVID vaccination has been changed to COVID-19 vaccination. • Demonstrated has been changed to found. 2. Please describe definition of variant of concern (VOC) duration. Response: Text has been added to clarify the time periods during which variants of concern circulated and the period during which they were studied (methods paragraph 4): VOCs circulated in British Columbia during the following approximate time periods: alpha (January – June 2021), gamma (February – July 2021), delta (May 2021 – December 2021) and omicron (December 2021 onwards) (17). Data were limited to these four dominant VOCs based on data availability and categorization used by the BCCDC Public Health Laboratory (PHL) during the study duration (March 2020 to October 2022). Please let us know if we did not satisfactorily describe the VOC duration with our response above. We would be happy to re-address this comment with further clarification on what VOC duration refers to. Reviewer Comments: No additional comments to address. Attachments Attachment Submitted filename: Reviewer Responses Round 2.docx https://doi.org/10.1371/journal.pone.0336929.r004
2 Nov 2025 Decision Letter - Dong Keon Yon, Editor Association between COVID-19 vaccination, SARS-CoV-2 variants, and post COVID-19 condition: a cross-sectional study PONE-D-25-00682R2 Dear Dr. El-Akkad, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Dong Keon Yon, MD, FACAAI, FAAAAI Academic Editor PLOS ONE Additional Editor Comments (optional): This is an excellent paper. Reviewers' comments: https://doi.org/10.1371/journal.pone.0336929.r005
Formally Accepted
Acceptance Letter - Dong Keon Yon, Editor PONE-D-25-00682R2 PLOS ONE Dear Dr. El-Akkad, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Dong Keon Yon Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0336929.r006

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