A prospective evaluation of Johnson & Johnson COVID-19 vaccine on glycemic biomarkers in type 2 diabetes mellitus in Ethiopia

Chala Kenenisa Edae; Abdisa Tufa Bedada; Maria Degef Teklemariam; Mesfin Bekele Tolesa; Solomon Genet Gebre

doi:10.1371/journal.pone.0340457

Peer Review History

Original SubmissionJuly 3, 2025
16 Sep 2025 Decision Letter - Timotius Hariyanto, Editor Dear Dr. Edae, 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 31 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'. 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, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Timotius Ivan Hariyanto, M.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 3. Thank you for stating the following financial disclosure: “This study was financially supported by Addis Ababa University and the Oromia Health Bureau.” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 4. In the online submission form, you indicated that “The data supporting the findings of this study are available from the authors upon reasonable request.” All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval. 5. 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. [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: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: No Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: No Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: No Reviewer #2: Yes ****** Reviewer #1: Manuscript ID: PONE-D-25-35535 Title: Prospective Assessment of Johnson & Johnson COVID-19 Vaccine Effects on Glycemic Biomarkers in Type 2 Diabetes Mellitus in Ethiopia General Evaluation This study investigates the effects of the Johnson & Johnson COVID-19 vaccine (Ad26.COV2.S) on glycemic biomarkers among patients with type 2 diabetes mellitus (T2DM) in Ethiopia. The authors conducted a prospective longitudinal study to compare glycemic trends between vaccinated and unvaccinated individuals with diabetes. The research is timely, relevant, and well-structured; however, there are several significant and minor issues that need to be addressed to enhance scientific rigor, interpretation, and contextualization. Major Comments Insufficient Prior Research on Glycemic Control and Vaccine Response The manuscript does not adequately reference key studies that demonstrate the direct relationship between glycemic control and the immunogenicity and efficacy of COVID-19 vaccines, particularly in patients with T2DM. Essential studies include: Marfella et al., Nat Commun (2022): This research indicates that poor glycemic control is associated with increased SARS-CoV-2 breakthrough infections post-vaccination among T2DM patients. Sardu et al., J Clin Med (2022): This study explores the pathophysiological mechanisms through which hyperglycemia may impair vaccine effectiveness and worsen illness severity. Marfella et al., Diabetes Obes Metab (2022): The CAVEAT Study examines the impact of glycemic control on the immunogenicity of COVID-19 vaccines in T2DM patients. Inclusion of these references in the Introduction and Discussion sections is crucial for accurately situating your findings within the existing body of literature. Clarification of HbA1c Trends The assertion that vaccination resulted in a “sustained increase” in HbA1c should be articulated with greater precision. Due to the non-randomized study design, it is difficult to eliminate the influence of baseline confounders or lifestyle changes. Although the Generalized Estimating Equations (GEE) model accounts for several covariates, it does not control for unmeasured confounders (e.g., dietary habits or exercise patterns). Control Group Assignment and Causal Inference As this study is a prospective cohort analysis, the control group (those not vaccinated) is self-selected, which introduces potential bias. Even retrospectively, methods such as Propensity Score Matching (PSM) or Inverse Probability Weighting (IPW) could be implemented to adjust for differences between the two groups. Absence of Immunological Markers While inflammatory cytokines (IL-6, TNF-α) are mentioned as mechanistic mediators, they are not measured in this study. This limitation should be explicitly acknowledged in the manuscript’s mechanistic interpretations. Terminology: “Improved” vs. “Increased” In multiple instances (e.g., Table 2 and the Discussion), the authors use the term “improved” to describe higher values of RBS or HbA1c. This terminology is misleading; it would be more accurate to state that these values are elevated, which typically indicates poorer glycemic control. Minor Comments Effect Size Clarification While using Cohen’s d is appropriate, it is important to contextualize this statistic in terms of clinical significance (e.g., what does an increase of 0.89% in HbA1c imply for patient risk?). Ethics Statement The ethics statement is well-written and adheres to the required guidelines. Figures All figures should be incorporated into the main body of the manuscript or supplementary materials for improved readability. Writing Quality The manuscript is generally well-composed; however, certain sections, particularly the Results, would benefit from professional copy-editing to enhance fluency. Recommendation Major Revision Suggested Citations for Inclusion Please consider including and discussing the following pivotal studies: Marfella R et al. Glycaemic control is related to SARS-CoV-2 breakthrough infections in vaccinated patients with type 2 diabetes. Nat Commun. 2022;13(1):2318. [PMID: 35484164] Sardu C et al. A summary of the impact of hyperglycemia on COVID-19 outcomes: Vaccines efficacy, disease severity and molecular mechanisms. J Clin Med. 2022;11(6):1564. [PMID: 35329890] Marfella R et al. Does the immunogenicity of the COVID-19 vaccination decrease in type 2 diabetic patients with poor glycaemic control: The CAVEAT study. Diabetes Obes Metab. 2022;24(1):160–165. [PMID: 34494705] Reviewer #2: Edae CK et al. investigated the impact of the Johnson & Johnson COVID-19 vaccine on glycemic parameters in patients with type 2 diabetes (T2D) in Ethiopia. They demonstrated that Johnson & Johnson COVID-19 vaccination was associated with short term Random Blood Sugar (RBS) fluctuations and a sustained increase in HbA1c levels, with more pronounced hyperglycemic alterations in younger individuals and female patients. Though the topic is potentially relevant, particularly in relatively understudied populations such as African populations, and the prospective design valuable, several substantial revisions are required before the manuscript can be considered for publication. Major Comments -Since this study was conducted in Ethiopia, it is important to discuss how these findings might translate to other contexts, particularly in higher-income countries where healthcare structures, diabetes management practices, and vaccination strategies differ significantly. Please, expand the discussion section relative to these aspects. -Another key limitation of the study is that glycemic variability was assessed through RBS levels rather than more robust methods such as continuous or flash glucose monitoring systems. Though this is likely related to resource constraints, this limitation should be clearly acknowledged and discussed. -Several important baseline characteristics of the study population are currently missing. I would strongly recommend providing a new detailed table (new Table 1) including for instance data on BMI, smoking status, other comorbidities such as prevalence of hypertension and diabetes-related complications, socioeconomic status, education level, baseline HbA1c levels and other relevant biochemical parameters (e.g. renal function tests), if available, and analyzing potential differences between vaccinated and unvaccinated groups at baseline according to these variables -Potentially important variables were not included in the multiple regression analyses. In particular, BMI and baseline HbA1c may both influence glycemic control and variability after vaccination. If available, these data should be incorporated into the model, otherwise their absence should be acknowledged as an additional limitation. -The conclusions could be expanded to include more practical clinical implications of the study findings. How should clinicians interpret these changes in glycemic levels post-vaccination? Should closer monitoring be advised in certain subgroups (e.g., younger individuals, women)? Please, better discuss this point. Minor Comments 1. Please consider adding a study flowchart figure. 2. Table 2 should be reformatted for greater clarity, with a more clearer separation of columns. 3. Please carefully revise the acronyms throughout the manuscript (e.g., Type 2 Diabetes Mellitus/T2DM, Hemoglobin A1c/HbA1c, Random Blood Sugar/RBS, Hypothalamic-Pituitary-Adrenal/HPA axis). ****** 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: Yes: Raffaele Marfella 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 . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0340457.r001
Revision 1
29 Sep 2025 Author Response We sincerely thank you, the Academic Editor, and the reviewers for your valuable time and constructive feedback on our manuscript. We have carefully revised the paper in line with all the points raised. Below, we provide a detailed, point-by-point response. Reviewer comments are restated in italics, followed by our responses and corresponding changes in the manuscript. Journal Requirements 1. Style requirements and file naming Comment: Please ensure manuscript follows PLOS ONE style templates. Response: We reformatted the manuscript according to PLOS ONE’s formatting requirements. File names for resubmission now follow the required conventions: • “Response to Reviewers” • “Revised Manuscript with highlight Changes” • “Manuscript” 2. Funding information mismatch Comment: The ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. Response: We corrected this discrepancy. The Funding section now clearly states: “There is no funding or grant received for this study.” 3. Role of funders Comment: Please clarify the role of funders. Response: “There is no funder for this study and therefore, no roles.” 4. Data availability policy Comment: All PLOS journals require underlying data to be freely available. Response: “All relevant data within the manuscript were uploaded with the title of supplementary files to be freely accessible.” 5. Citing suggested studies Comment: Reviewers recommended citing additional work. Response: We incorporated the following references in the study: • Marfella R et al., Nat Commun 2022. • Sardu C et al., J Clin Med 2022. • Marfella R et al., Diabetes Obes Metab 2022. Reviewer #1 Major Comments 1. Insufficient prior research on glycemic control and vaccine response. Response: We revised the Introduction and Discussion to integrate the suggested studies and explain how poor glycemic control may impact vaccine immunogenicity and outcomes. 2. Clarification of HbA1c trends. Response: We rephrased the Results and Discussion to state “elevated HbA1c levels were observed” rather than “sustained increase,” and emphasized potential influence of unmeasured confounders despite the GEE adjustments. 3. Control group assignment bias. Response: We acknowledged the non-randomized nature of the study and discussed potential bias due to self-selection. Additionally, we included the need to conduct sensitivity analysis using Propensity Score Matching (PSM) to adjust for baseline differences as a limitation of the study. 4. Absence of immunological markers. Response: We explicitly acknowledged this limitation in the Discussion and clarified that mechanistic interpretations remain speculative. 5. Terminology: “improved” vs. “increased.” Response: We revised all instances of “improved” to “elevated” or “increased” when describing RBS and HbA1c. Minor Comments • Effect size clarification: We added a discussion on the clinical significance of HbA1c changes. • Figures: All figures are now embedded in the main text and also available as supplementary files. • Writing quality: We edited the Results section for clarity and fluency. Reviewer #2 Major Comments 1. Contextualization to other settings. Response: We expanded the Discussion to compare findings in Ethiopia with potential implications for high-income countries, where healthcare infrastructure and vaccination strategies differ. 2. Limitation: RBS vs. continuous glucose monitoring. Response: We acknowledged that RBS is a less robust marker than continuous or flash glucose monitoring, but explained this was due to resource limitations in our setting. 3. Expanded clinical implications. Response: The Conclusion now advises that clinicians may consider closer glycemic monitoring post-vaccination in younger and female T2DM patients, particularly those with poor baseline glycemic control. Minor Comments 1. Table 2 formatting: Reformatted for clarity with improved column separation. 2. Acronyms: Revised throughout the manuscript for consistency. Conclusion We believe that the revised manuscript has significantly improved in scientific rigor, contextualization, and clarity following the reviewers’ helpful comments. We are grateful for the opportunity to resubmit and look forward to your further consideration. Sincerely, Chala Kenenisa Edae Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0340457.r002
15 Dec 2025 Decision Letter - Timotius Hariyanto, Editor Dear Dr. Edae, 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 Jan 29 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 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 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'. 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 applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Timotius Ivan Hariyanto, M.D. 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #3: Yes ****** Reviewer #1: The manuscript has been further improved and refined for clarity and overall quality. Overall, the scientific message is ok Reviewer #3: Minor Comments In the Introduction, condense lines 1–3 to avoid repetition of global DM prevalence. Define all abbreviations (e.g., GEE, PSM) at first mention. Correct small typos: “uninfected group” → “unvaccinated group.” Consider adding 95 % CI ribbons or error bars to trend figures for clarity. ****** 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: Yes: Raffaele Marfella Reviewer #3: Yes: Elabbass Ali Abdelmahmuod ******** [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.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0340457.r003
Revision 2
16 Dec 2025 Author Response Response to Review Comments We thank the reviewers for their careful review and constructive feedback, which have helped improve the clarity and quality of the manuscript. We address the comments below. Reviewer #1 Comment: The manuscript has been further improved and refined for clarity and overall quality. Overall, the scientific message is acceptable. Response: We thank the reviewer for the positive assessment of the manuscript and for acknowledging the improvements made. We are pleased that the scientific message is considered sound. Reviewer #3 – Minor Comments Comment: Condense lines 1–3 of the Introduction to avoid repetition of global DM prevalence. Response: The Introduction has been revised to condense lines 1–3 and remove repetitive statements on global diabetes mellitus prevalence. Comment: Define all abbreviations (e.g., GEE, PSM) at first mention. Response: All abbreviations, including GEE (Generalized Estimating Equations) and PSM (Propensity Score Matching), are now defined at first mention in the text. Comment: Correct the typo “uninfected group” to “unvaccinated group.” Response: This typographical error has been corrected throughout the manuscript. Comment: Consider adding 95% confidence interval ribbons or error bars to trend figures. Response: Trend figures have been updated to include 95% confidence intervals where appropriate to improve clarity and interpretability We appreciate the reviewers’ suggestions, which have strengthened the manuscript. Attachments Attachment Submitted filename: Response to Review Comments.docx https://doi.org/10.1371/journal.pone.0340457.r004
22 Dec 2025 Decision Letter - Timotius Hariyanto, Editor A Prospective Evaluation of Johnson & Johnson COVID-19 Vaccine on Glycemic Biomarkers in Type 2 Diabetes Mellitus in Ethiopia PONE-D-25-35535R2 Dear Dr. Edae, 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, Timotius Ivan Hariyanto, M.D. Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0340457.r005
Formally Accepted
Acceptance Letter - Timotius Hariyanto, Editor PONE-D-25-35535R2 PLOS One Dear Dr. Edae, 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. Timotius Ivan Hariyanto Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0340457.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .