Influence of nutritional supplements on antibody levels in pregnant women vaccinated with inactivated SARS-CoV-2 vaccines

Xi Zhang; Xue Han; Baolan Chen; Xi Fu; Yajie Gong; Wenhan Yang; Qingsong Chen

doi:10.1371/journal.pone.0289255

Peer Review History

Original SubmissionJuly 14, 2023
7 Aug 2023 Decision Letter - Gang Qin, Editor PONE-D-23-21116Effects of nutritional supplements on antibody levels in pregnant women vaccinated with inactivated SARS-CoV-2 vaccinesPLOS ONE Dear Dr. CHEN, 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 Sep 21 2023 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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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: No Reviewer #2: Yes ******** 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 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: No 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: This manuscript presents a study that enrolled 873 pregnant women to investigate their general demographic characteristics and the use of nutritional supplements, specifically in relation to the serum antibody levels induced by inactivated SARS-CoV-2 vaccines. While the article attempts to explore the association between nutritional supplements and immune effects of these vaccines during pregnancy, the research significance of this relationship is not clearly discussed. The introduction of the article dedicates considerable space to emphasizing the significance of nutritional supplements for pregnant women, but only briefly mentions the immunomodulatory effects of nutrients in the context of COVID-19 susceptibility. This lack of clarity in the study's objective left me uncertain about the authors' intentions. Overall, the manuscript fails to demonstrate the advantages and necessity of the study, resulting in a lack of novel and significant results. As a result, I do not recommend this manuscript for publication in PLOS ONE. Major concerns: 1. The meaning of the reported P values in Table 1 and Table 3 is unclear. For example, if the P value in line "Age group" (Table 1, 0.054) indicates that there are no significant differences between the folic acid group and non-folic acid group in terms of age, then how should we interpret the P value in line "Doses of vaccination" (Table 3, <0.001)? It suggests that there is a significant difference between the neutralizing antibody positive group and neutralizing antibody negative group in terms of vaccination doses. However, in lines 201-203, the authors conclude that "For pregnant women who took folic acid, the positive rate of SARS-CoV-2 neutralizing antibody varied significantly with vaccine doses (P < 0.001) and time since vaccination (P < 0.001)." Such inconsistencies are present throughout the article. If the P values have different implications in different tables, the authors should provide clear explanations in the manuscript. 2. In lines 186-187, the authors state "We found significant differences in gravidity (P = 0.002), parity (P = 0.012), and education (P = 0.008) according to whether the pregnant women took folic acid." The intended meaning of this statement is unclear. Similar sentences also appear on lines 190-193. 3. In Table 6, the authors adjusted for variables such as age, BMI, education, number of exercises per week, adverse events, inoculation durations, and doses of vaccination. The rationale behind selecting these variables and not others is not explained. Additionally, the manuscript lacks univariate analysis of these variables in relation to antibody levels. Reviewer #2: This study aimed to examine the influence of dietary supplements on antibody levels in pregnant women vaccinated with inactivated SARS-CoV-2 vaccine. Because it is a cross-sectional study, it is better to use “influence” than “effect”, which may imply a causal association. Overall, this study is well written and seems to add to the literature timely. There are some comments that can be considered for further publication. Page 5, add citation for “Pregnant women with iron deficiency anemia are more susceptible to SARS-CoV-2 infection.” Page 5, in the last paragraph of the introduction, please show how this study add to the literature. Page 5, add a flowchart for the study participants Page 6, in the study variable section, try to make clear that which variables are outcome variables, exposure variables, and covariates, respective. Page 7, justify why fisher test are needed. Page 12, line 200, authors further analyzed the general demographic characteristics of the pregnant women taking the three nutritional supplements separately. Tables 3-5 can be combined to one Table. Also, these tables seem not quite contribute well to the study aim, which can be considered to be the supplemental Table. Page 20, page 283, it is better to use "multivariable analysis", rather than "multivariate analysis". Page 21, Table 6 is the final model to answer the study aim. In bivariate analyses, the associations between exposure variables (e.g., iron supplements and DHA) and outcome variables seems to be statistically significant but the associations disappeared in the adjusted models. Any reasons? For each model based on three separate exposure variables, whether authors adjusted for different confounding factors (e.g., see Table 1)? What is the definition of the confounder? Also, are there any effect modifiers? In the statistic analysis section, authors can provide more details. Page 21, in discussion section, any previous studies in China or worldwide have been done? Are their findings consistent with the present study? Try to add some novelty/strength of this study. ****** 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.0289255.r001
Revision 1
24 Aug 2023 Author Response Aug 13, 2023 Dear Editor, Thank you for providing us this opportunity to revise our manuscript entitled “Effects of nutritional supplements on antibody levels in pregnant women vaccinated with inactivated SARS-CoV-2 vaccines” (Manuscript ID: PONE-D-23-21116). On behalf of my colleagues, I am submitting our revised manuscript. We appreciate the reviewers’ and editor’s positive and insightful comments. We have carefully considered all the comments and revised the manuscript accordingly. In order to facilitate the review process, we provided a point-by-point response to each of the comments. The precise page and line in the revised manuscript where each change was made in response to the comments were provided as well. We appreciated for Editors and Reviewers’ warm work earnestly. We have tried our best to improve and revise the manuscript. We hope that the manuscript is now acceptable. Should you have any additional requests or questions, please do not hesitate to contact me. We look forward to hearing from you. RESPONSES TO THE REVIEWER#1’ S COMMENTS Comment 1: The meaning of the reported P values in Table 1 and Table 3 is unclear. For example, if the P value in line "Age group" (Table 1, 0.054) indicates that there are no significant differences between the folic acid group and non-folic acid group in terms of age, then how should we interpret the P value in line "Doses of vaccination" (Table 3, <0.001)? It suggests that there is a significant difference between the neutralizing antibody positive group and neutralizing antibody negative group in terms of vaccination doses. However, in lines 201-203, the authors conclude that "For pregnant women who took folic acid, the positive rate of SARS-CoV-2 neutralizing antibody varied significantly with vaccine doses (P < 0.001) and time since vaccination (P < 0.001)." Such inconsistencies are present throughout the article. If the P values have different implications in different tables, the authors should provide clear explanations in the manuscript. Response: Thanks for the reviewer's comment. As you mentioned above，the P value in line "Doses of vaccination" (Table 3, <0.001) suggests that there is a significant difference between the neutralizing antibody positive group and neutralizing antibody negative group in terms of vaccination doses. I'm sorry for not expressing clearly.We have revised (show in line 212-226) as: For pregnant women who took folic acid, there was a significant difference between the neutralizing antibody positive group and neutralizing antibody negative group in terms of vaccination doses (P < 0.001) and time since vaccination (P < 0.001). There was a significant difference between IgG antibody negative and positive groups in terms of age (P = 0.025), adverse events (P = 0.027), vaccination doses (P < 0.001), and time since vaccination (P < 0.001). Among pregnant women who took iron, there was a significant difference between the negative and positive groups of neutralizing antibody, as well as the negative and positive groups of IgG antibody, in terms of vaccination doses (P < 0.001). In pregnant women taking DHA, there was a significant difference between IgG antibody negative and positive groups in terms of gravidity (P = 0.040), vaccination doses (P < 0.001), and time since vaccination (P < 0.001). There was a statistically significant difference between the neutralizing antibody positive group and neutralizing antibody negative group in terms of vaccination doses (P < 0.001) and time since vaccination (P = 0.009) . Comment 2: In lines 186-187, the authors state "We found significant differences in gravidity (P = 0.002), parity (P = 0.012), and education (P = 0.008) according to whether the pregnant women took folic acid." The intended meaning of this statement is unclear. Similar sentences also appear on lines 190-193. Response: Thanks for the reviewer's comment. We have revised (show in line 196-198,200-204) as: We found that there were statistically significant differences between groups of pregnant women who did or did not take folic acid in terms of gravidity (P = 0.002), parity (P = 0.012), and education (P = 0.008). There were statistically significant differences between groups of pregnant women who did or did not take iron supplements in terms of smoking (P = 0.008), weekly exercise frequency (P < 0.001), vaccine doses (P < 0.001), time since vaccination (P < 0.001), SARS-CoV-2 neutralizing antibody (P = 0.017), and IgG antibody (P < 0.001) . Comment 3:In Table 6, the authors adjusted for variables such as age, BMI, education, number of exercises per week, adverse events, inoculation durations, and doses of vaccination. The rationale behind selecting these variables and not others is not explained. Additionally, the manuscript lacks univariate analysis of these variables in relation to antibody levels. Response: Thanks for the reviewer's comment. We have revised (show in line 167-173) as: The adjusted factors were determined through the results of univariate analysis and literature review. Model 1 was adjusted for age, BMI, education, gravidity, parity, adverse events, inoculation durations, doses of vaccination. Model 2 was adjusted for age, BMI, smoking, number of exercises per week, adverse events, inoculation durations, doses of vaccination. Model 3 was adjusted for age, BMI, smoking, number of exercises per week, adverse events, inoculation durations, doses of vaccination. RESPONSES TO THE REVIEWER#2’ S COMMENTS Comment 4: Page 5, add citation for“Pregnant women with iron deficiency anemia are more susceptible to SARS-CoV-2 infection.” Response: Thanks for the reviewer's comment.We have added citation for the word. Comment 5: Page 5, in the last paragraph of the introduction, please show how this study add to the literature. Response: Thanks for the reviewer's comment.We have revised (show in line 113-115) as: This study can provide a certain reference for the question of the influence of women taking nutrients during pregnancy on the level of antibody produced by COVID-19 vaccines. Comment 6: Page 5, add a flowchart for the study participants. Response: Thanks for the reviewer's comment.We have added a flowchart in page 6. Comment 7: Page 6, in the study variable section, try to make clear that which variables are outcome variables, exposure variables, and covariates, respective. Response: Thanks for the reviewer's comment.We have revised (show in line 140-143) as: The presence of nutrient supplements was the exposure variable, negative or positive antibody level were outcome variables, and age, BMI, parity, education and income level, smoking, number of exercises per week, doses of vaccination, adverse reactions, and time since vaccination were covariates. Comment 8: Page 7, justify why fisher test are needed. Response: Thanks for the reviewer's comment.We have revised (show in line 164) as: When the sample size n < 40 or the expected frequency T < 1 use Fisher's test. Comment 9: Page 12, line 200, authors further analyzed the general demographic characteristics of the pregnant women taking the three nutritional supplements separately. Tables 3-5 can be combined to one Table. Also, these tables seem not quite contribute well to the study aim, which can be considered to be the supplemental Table. Response: Thanks for the reviewer's comment.We have revised. Comment 10: Page 20, page 283, it is better to use "multivariable analysis", rather than "multivariate analysis". Response: Thanks for the reviewer's comment.We have revised (show in line 230) . Comment 11: Page 21, Table 6 is the final model to answer the study aim. In bivariate analyses, the associations between exposure variables (e.g., iron supplements and DHA) and outcome variables seems to be statistically significant but the associations disappeared in the adjusted models. Any reasons? For each model based on three separate exposure variables, whether authors adjusted for different confounding factors (e.g., see Table 1)? What is the definition of the confounder? Also, are there any effect modifiers? In the statistic analysis section, authors can provide more details. Response: Thanks for the reviewer's comment.We have revised (show in line 167-173) as: The adjusted factors were determined through the results of univariate analysis and literature review. Model 1 was adjusted for age, BMI, education, gravidity, parity, adverse events, inoculation durations, doses of vaccination. Model 2 was adjusted for age, BMI, smoking, number of exercises per week, adverse events, inoculation durations, doses of vaccination. Model 3 was adjusted for age, BMI, smoking, number of exercises per week, adverse events, inoculation durations, doses of vaccination. Comment 12: Page 21, in discussion section, any previous studies in China or worldwide have been done? Are their findings consistent with the present study? Try to add some novelty/strength of this study. Response: Thanks for the reviewer's comment.We have revised (show in line 335-338) as: The strength of this study is that it is the first to examine the influence of nutrient supplements taken during pregnancy on the antibody level produced by pregnant women who have received COVID-19 vaccines. The finding of this study provides a certain degree of reference for pregnant women in this regard. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0289255.r002
4 Sep 2023 Decision Letter - Gang Qin, Editor Influence of nutritional supplements on antibody levels in pregnant women vaccinated with inactivated SARS-CoV-2 vaccines PONE-D-23-21116R1 Dear Dr. CHEN, 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, Gang Qin, PhD, MD Academic Editor PLOS ONE Additional Editor Comments (optional): The authors have addressed all of the reviewers' concerns. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: All comments have been addressed ******** 2. 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 #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 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 #2: Yes ****** 5. 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 #2: Yes ****** 6. 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 #2: Authors have addressed my comments and revised accordingly in the main text. Additionally, revised tables are improved to satisfy the study aims. ****** 7. 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 #2: No ******** https://doi.org/10.1371/journal.pone.0289255.r003
Formally Accepted
27 Feb 2024 Acceptance Letter - Gang Qin, Editor PONE-D-23-21116R1 PLOS ONE Dear Dr. Chen, 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 If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks 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. 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. Gang Qin Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0289255.r004

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