Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review

Julie Perry; Selma Osman; James Wright; Melissa Richard-Greenblatt; Sarah A. Buchan; Manish Sadarangani; Shelly Bolotin

doi:10.1371/journal.pone.0266852

Peer Review History

Original SubmissionFebruary 10, 2022
9 Mar 2022 Decision Letter - Victor C Huber, Editor PONE-D-22-03976 Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review PLOS ONE Dear Dr. Bolotin, 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. During the revision process, please address the minor revisions recommended by the reviewers. Please submit your revised manuscript by Apr 21 2022 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. 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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. Thank you for stating the following financial disclosure: “This work was supported by Public Health Ontario and funding from the Public Health Agency of Canada to SB. NO” 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. 3. Thank you for stating the following in the Acknowledgments Section of your manuscript: “This work was supported by Public Health Ontario and funding from the Public Health Agency of Canada.” We note that you have provided funding information that is not currently declared in your Funding Statement. However, 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: “This work was supported by Public Health Ontario and funding from the Public Health Agency of Canada to SB. NO” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 4. Thank you for stating the following in your Competing Interests section: “NO” Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state ""The authors have declared that no competing interests exist."", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. 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 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). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. 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: The authors performed a literature review trying to determine the CoP for SARS-CoV-2 by compiling serological data on reinfections or vaccine breakthrough infections previously reported in publications or preprints. They found that while no absolute threshold for CoP can be determined up to this point, the correlate appears to be relative in a way that higher serological antibody levels in response to vaccination or infection yield greater protection against SARS-CoV-2 infection. The manuscript is very well written, but its greatest strength lies not in its findings or conclusions which are fairly generic and previously reported on, but in the vast compendium of publications they found and assessed that have attempted correlating protection against SARS-CoV-2 with serological measures. The authors are well aware of the limitations, most of which stem from the fact that there is simply too much variables in the studies – the assays and units used, the types of vaccines, and the variants causing the re-infections or breakthrough infections. The authors allude to the fact that the CoP may be different between vaccine manufacturers and variants and no single answer can be found – that is certainly the case. The authors also reported contradictory patterns from individual case studies regarding patterns between reinfection/breakthrough rates and prior antibody levels; this is not surprising as most case studies are different from the average (why they were deemed interesting as stand-alone cases) and should at most be weighted the same as a participant in a cohort study. Overall, the publication has merit as the tables serve as a useful reference guide for SARS-CoV-2 researchers and the authors are well aware of the limitations of the study. I recommend the review for publication. Reviewer #2: This paper is a review of serological correlates of protection for COVID-19 vaccines. The review is competent and complete. It reaches the conclusion that nearly everybody else has: that antibodies, particularly neutralizing, correlate with efficacy. It emphasizes that the correlate is relative, that is there is no level that corresponds to 100% efficacy. That conclusion is expected in view of published data and the fact that SARS-2 infection is primarily mucosal, similar to influenza, for which as the authors themselves say antibody is the correlate of protection although the protective level of antibody increases with titer but no absolute level is reached.. So the last line of the discussion “we do not have the tools to interpret serology with regards to protection” is silly, inasmuch as the authors describe how higher levels correlate with protection. Of course, cellular and Fc Effector immunity undoubtedly also have a role, but that does not gainsay the major role of antibody. It is also worth emphasizing that homologous levels have to be determined for each SARS-2 variant. On a trivial note, in line 162 “sera” is a plural noun and therefore “are”. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). 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Revision 1
24 Mar 2022 Author Response 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. The manuscript has been reformatted according to PLOS style requirements. 2. Thank you for stating the following financial disclosure: “This work was supported by Public Health Ontario and funding from the Public Health Agency of Canada to SB. NO” 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. A Role of Funder statement is now included in our cover letter 3. Thank you for stating the following in the Acknowledgments Section of your manuscript: “This work was supported by Public Health Ontario and funding from the Public Health Agency of Canada.” We note that you have provided funding information that is not currently declared in your Funding Statement. However, 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: “This work was supported by Public Health Ontario and funding from the Public Health Agency of Canada to SB. NO” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. All funding-related statements have been removed from the text and included in the Cover letter and Funding statement. Please use the Funding Statement as previously submitted. 4. Thank you for stating the following in your Competing Interests section: “NO” Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state ""The authors have declared that no competing interests exist."", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. Cover letter now includes conflict of interest disclosure, which has been removed from the text. Reviewer comments (Responses in Bold/Italics) Reviewer #1: The authors performed a literature review trying to determine the CoP for SARS-CoV-2 by compiling serological data on reinfections or vaccine breakthrough infections previously reported in publications or preprints. They found that while no absolute threshold for CoP can be determined up to this point, the correlate appears to be relative in a way that higher serological antibody levels in response to vaccination or infection yield greater protection against SARS-CoV-2 infection. The manuscript is very well written, but its greatest strength lies not in its findings or conclusions which are fairly generic and previously reported on, but in the vast compendium of publications they found and assessed that have attempted correlating protection against SARS-CoV-2 with serological measures. The authors are well aware of the limitations, most of which stem from the fact that there is simply too much variables in the studies – the assays and units used, the types of vaccines, and the variants causing the re-infections or breakthrough infections. The authors allude to the fact that the CoP may be different between vaccine manufacturers and variants and no single answer can be found – that is certainly the case. The authors also reported contradictory patterns from individual case studies regarding patterns between reinfection/breakthrough rates and prior antibody levels; this is not surprising as most case studies are different from the average (why they were deemed interesting as stand-alone cases) and should at most be weighted the same as a participant in a cohort study. Overall, the publication has merit as the tables serve as a useful reference guide for SARS-CoV-2 researchers and the authors are well aware of the limitations of the study. I recommend the review for publication. We thank the reviewer for their time and their expert appraisal of our manuscript. Reviewer #2: This paper is a review of serological correlates of protection for COVID-19 vaccines. The review is competent and complete. It reaches the conclusion that nearly everybody else has: that antibodies, particularly neutralizing, correlate with efficacy. It emphasizes that the correlate is relative, that is there is no level that corresponds to 100% efficacy. That conclusion is expected in view of published data and the fact that SARS-2 infection is primarily mucosal, similar to influenza, for which as the authors themselves say antibody is the correlate of protection although the protective level of antibody increases with titer but no absolute level is reached.. So the last line of the discussion “we do not have the tools to interpret serology with regards to protection” is silly, inasmuch as the authors describe how higher levels correlate with protection. Of course, cellular and Fc Effector immunity undoubtedly also have a role, but that does not gainsay the major role of antibody. It is also worth emphasizing that homologous levels have to be determined for each SARS-2 variant. On a trivial note, in line 162 “sera” is a plural noun and therefore “are”. We thank the reviewer for their time and their expert appraisal of our manuscript. We have removed the last line of the discussion, and also changed line 162 (now line 163) to reflect “sera” as plural. We have also added further emphasis to the variant-specific nature of a CoP in lines 281-283. Attachments Attachment Submitted filename: Response to reviewers 2022_03_24.docx https://doi.org/10.1371/journal.pone.0266852.r002
29 Mar 2022 Decision Letter - Victor C Huber, Editor Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review PONE-D-22-03976R1 Dear Dr. Bolotin, 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, Victor C Huber Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0266852.r003
Formally Accepted
31 Mar 2022 Acceptance Letter - Victor C Huber, Editor PONE-D-22-03976R1 Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review Dear Dr. Bolotin: 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. Victor C Huber Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0266852.r004

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