Evolution of antibody titers after two doses of mRNA Pfizer-BioNTech vaccine and effect of the third dose in nursing home residents

Iciar Rodríguez-Avial; Cristina García-Salguero; Laura Bermejo; Juan Teja; Elisa Pérez-Cecilia; Alberto Delgado-Iribarren; Marta Vigara; Pedro Gil; Esther Culebras

doi:10.1371/journal.pone.0282388

Peer Review History

Original SubmissionNovember 21, 2022
10 Jan 2023 Decision Letter - Gheyath K. Nasrallah, Editor PONE-D-22-32111Evolution of antibody titers after two doses of mRNA Pfizer-BioNTech vaccine and effect of the third dose in nursing home residentsPLOS ONE Dear Dr. Culebras, 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 24 Feb 2023. 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. 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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? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. 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 requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Dear Author, I have some concern to highlight. 1. I would appreciate a better definition of the cohort of patient in relation to the data derived from each group. (i.e.: data after six month, cellular response data) 2-Results, line 37: better specify a positive SEROLOGICAL response. 3-Introduction, line 83: you wrote that data after third dose have been collected from another group and not from the original cohort of residents. But don't you think this could influence the rate of decrease? I mean, considering the residents are people at risk, with several pathologies, the IgG trend could be significantly different. 4-Antibody Testing, line112: you wrote SpikeIgG, better specify RBD, as the Abbott test refers to these last antibodies. 5- line 154: you wrote recorder, may be it was recorded. 6- Why cellular response was determined only in 24 patients? Did you get a cut-off value of RBD Abs titer in relation to cellular response? 7- My main concern is on Abs measurements unit. All these data should be given in BAU/ml, as globally stated for spike IgG. Reviewer #2: The authors (AA) aim to evaluate the antibody response against SARS-CoV-2 during 6 months after the second dose of the Pfizer-BioNTech vaccine in a cohort of residents of a Spanish nursing home. This is an engaging article with a study design appropriate and useful to increase our knowledge of the issue. The title reports the key features of the paper encouraging the reader to read more. Introduction Lines 76: AA could add some references about healthcare workers in the same setting and other healthcare facilities, such as: Hall, V.J.; Foulkes, S.; Saei, A.; Andrews, N.; Oguti, B.; Charlett, A.; Wellington, E.; Stowe, J.; Gillson, N.; Atti, A.; et al. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): A prospective, multicentre, cohort study. Lancet 2021, 397, 1725–1735. Modenese, A.; Paduano, S.; Bellucci, R.; Marchetti, S.; Bruno, F.; Grazioli, P.; Vivoli, R.; Gobba, F.; Bargellini, A. Investigation of Possible Factors Influencing the Neutralizing Anti-SARS-CoV-2 Antibody Titer after Six Months from the Second Vaccination Dose in a Sample of Italian Nursing Home Personnel. Antibodies 2022, 11, 59. Modenese, A.; Paduano, S.; Bargellini, A.; Bellucci, R.; Marchetti, S.; Bruno, F.; Grazioli, P.; Vivoli, R.; Gobba, F. Neutralizing Anti-SARS-CoV-2 Antibody Titer and Reported Adverse Effects, in a Sample of Italian Nursing Home Personnel after Two Doses of the BNT162b2 Vaccine Administered Four Weeks Apart. Vaccines (Basel). 2021 Jun 15;9(6):652. Favresse, J.; Bayart, J.L.; Mullier, F.; Dogné, J.M.; Closset, M.; Douxfils, J. Early antibody response in healthcare professionals after two doses of SARS-CoV-2 mRNA vaccine (BNT162b2). Clin. Microbiol. Infect. 2021 Sep;27(9):1351.e5-1351.e7. Materials and methods Lines 105-107: AA could add the questionnaire as supplementary information. Did AA asked when the subjects contract SARS-CoV-2 infection? Lines 133-139: AA should move this paragraph before paragraph of statistical analysis. Results Table 1: Explain acronyms PI / NI. Moreover, it is not clear what is the statistical analysis AA performed. Clarify column IgG GM. Figure 1 and 2: Explain acronym PI / NI. AA could perform an analysis stratified the population according when they contract the infection. Discussion AA should better discuss their results in light of the available literature. Could the time elapsed since the infection influence the antibody titre detected at the time of the serological test? ****** 6. 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 ******** [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.0282388.r001
Revision 1
11 Feb 2023 Author Response Response to Reviewers´: Journal 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. The manuscript has been revised to meet the PLOS ONE style requirements. 2. Please expand the acronym “CM” (as indicated in your financial disclosure) so that it states the name of your funders in full. This information should be included in your cover letter; we will change the online submission form on your behalf." The acronym CM stands for Community of Madrid. The financial support should be: This study was supported by the Community of Madrid and the European Union, through the European Regional Development Fund (ERDF), supported as part of the Union’s response to the COVID-19 pandemic (PROYECTO REACT-EU INMUNOVACTER-CM). 3. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. The sentence that included “data not shown” was removed in this new version as these data are not a core part of the research. 4. 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. All references (previous and news) have been revised to ensure that they are complete and correct. Reviewer #1: 1. I would appreciate a better definition of the cohort of patient in relation to the data derived from each group. (i.e.: data after six month, cellular response data) The new version of the manuscript has included a description of the patients included in the analysis of antibody titers at six months and of those in whom the cellular response was determined. 2-Results, line 37: better specify a positive SEROLOGICAL response. Sentence has been rewritten to include SEROLOGICAL as per reviewer suggestion 3-Introduction, line 83: you wrote that data after third dose have been collected from another group and not from the original cohort of residents. But don't you think this could influence the rate of decrease? I mean, considering the residents are people at risk, with several pathologies, the IgG trend could be significantly different. The cohort was the same throughout the study, but the number of people decreased slightly over time, as 30 residents dropped out of the study for different reasons (their own decision or that of their relatives, deterioration of their health, or exitus). Initially, 196 nursing home residents were included. During the first 6 months, 30 of these participants dropped out of the analysis. The remaining 166 residents continued in the study for up to six months and were tested for antibody levels at this time. A group of nursing home staff and volunteers older than 65 years who lived outside the institution were used as comparison groups. This point has been explained in materials and methods (lines 97-98 and lines 109-110). Also, in Introduction line 83, a full stop is inserted to clarify that the cohort of nursing home residents is the same throughout the study and that the other two groups are only comparison groups at six months. 4-Antibody Testing, line112: you wrote SpikeIgG, better specify RBD, as the Abbott test refers to these last antibodies. Sentence has been corrected. 5- line 154: you wrote recorder, may be it was recorded. It has been corrected. 6- Why cellular response was determined only in 24 patients? Did you get a cut-off value of RBD Abs titer in relation to cellular response? The 24 selected patients are a representative sample of all the residents included in the studyThey cover the entire range of anti-RBD antibody titer found in the study (from 0 to >80000 AU/mL or 0 to >11360 BAU/mL). Both, patients with previous infection and patients initially considered naïve were included. Male and female and people of different ages are also represented. A paragraph has been included in Materials and methods (Memory T cell response) to describe the characteristics of these patients. 7- My main concern is on Abs measurements unit. All these data should be given in BAU/ml, as globally stated for spike IgG. Antibody titers have been changed to BAU/mL throughout the manuscript as suggested by the reviewer. Reviewer #2: Lines 76: AA could add some references about healthcare workers in the same setting and other healthcare facilities. References suggested by the reviewer have been included in the manuscript. Materials and methods Lines 105-107: AA could add the questionnaire as supplementary information. Did AA asked when the subjects contract SARS-CoV-2 infection? The questionnaire is now included as supplementary information. The question about the date of infection by SARS-CoV-2 was not answered by the majority of the residents, so it was not considered for the data analysis. The information on the underlying diseases and the side effects of the vaccines was completed in most cases by the staff of the residence Lines 133-139: AA should move this paragraph before paragraph of statistical analysis. The paragraph of memory T cell response has been moved before the paragraph of statistical analysis. Explain acronyms PI / NI. Moreover, it is not clear what is the statistical analysis AA performed. Clarify column IgG GM. The meaning of PI, NI and GM is now found in the footnotes of table I. Figure 1 and 2: Explain acronym PI / NI. That has been done AA could perform an analysis stratified the population according when they contract the infection. The exact date on which each resident contracted the SARS-CoV-2 infection was not answered by most of them, so this data has not been considered in the statistical analysis. However, the residence staff informed us that all of them had been infected in the first wave of the pandemic. Discussion AA should better discuss their results in light of the available literature. Several paragraphs have been included in discussion section Could the time elapsed since the infection influence the antibody titre detected at the time of the serological test? The time elapsed since the infection can influence the antibody titer, as indicated by other authors. Since we do not know the exact date of individual infection, this aspect cannot be confirmed with our data. A new paragraph has been included in the discussion section to explain this point. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0282388.r002
14 Feb 2023 Decision Letter - Gheyath K. Nasrallah, Editor Evolution of antibody titers after two doses of mRNA Pfizer-BioNTech vaccine and effect of the third dose in nursing home residents PONE-D-22-32111R1 Dear Dr. Culebras, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Gheyath K. Nasrallah Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0282388.r003
Formally Accepted
27 Feb 2023 Acceptance Letter - Gheyath K. Nasrallah, Editor PONE-D-22-32111R1 Evolution of antibody titers after two doses of mRNA Pfizer-BioNTech vaccine and effect of the third dose in nursing home residents Dear Dr. Culebras: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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. If we can help with anything else, please email us at plosone@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. Gheyath K. Nasrallah Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0282388.r004

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