Cost-effectiveness of varicella and herpes zoster vaccination in Sweden: An economic evaluation using a dynamic transmission model

Ellen Wolff; Katarina Widgren; Gianpaolo Scalia Tomba; Adam Roth; Tiia Lep; Sören Andersson

doi:10.1371/journal.pone.0251644

Peer Review History

Original SubmissionAugust 28, 2020
7 Oct 2020 Decision Letter - Georges M.G.M. Verjans, Editor PONE-D-20-26903 Cost-effectiveness of varicella and herpes zoster vaccination in Sweden: an economic evaluation using a dynamic transmission model PLOS ONE Dear Dr. Wolff, 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 within 3 months from now. 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. Please include the following items when submitting your revised manuscript: 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Georges M.G.M. Verjans, MSc, PhD Academic Editor PLOS ONE Additional Editor Comments: The MS submitted by Wolff E. et al. describes the use of a mathematical model to determine if varicella and/of herpes zoster vaccination is cost-effective to be introduced in the national vaccination program of Sweden. The study is well designed and of interest, but needs significant improvement for the general reader to appreciate the modelling applied and to discuss the data obtained in more detail. 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. Please amend your manuscript to include your abstract after the title page. 3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. [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: Partly ******** 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: No ****** 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: No ****** 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 should clearly state that zoster can be caused by the live attenuated varicella vaccine virus. This point is never clearly stated anywhere in the manuscript. Suggest 2 additional references be added at these locations. [1] Discussion, line 301. "The number of cases of herpes zoster will never go to zero, even after universal varicella vaccination. There will always be a few cases of herpes zoster caused by reactivation of latent varicella vaccine virus. " Please cite 2 references: PMID: 30496366 by Harpaz (2019) and PMID: 32677551 by Ramachandran (2020). [2] Discussion, lines 417-8. "There will always be a low background of herpes zoster in Sweden from reactivation of latent varicella vaccine virus in immunized citizens." Cite same 2 references. Reviewer #2: In the report by Wolff et al submitted to PLOS One a predictive study is presented from a number of assumptions that models the cost effectiveness of varicella and HZ vaccination in Sweden, using a rather not well explained or fully documented dynamic transition model. Based on the assumptions and modeling the authors conclude that the varicella vaccination program has a much stronger cost effectiveness, when given with or without the live zoster vaccination program. The live zoster vaccination program seems to only have a mild effect on incidence and cost effectiveness that leads them to conclude it is not cost effective. This is different from most of the cost effectiveness studies from other countries, which generally indicate a zoster vaccine would be cost effective. This review is given by a person knowledgeable in the field of varicella and zoster who is not a statistical epidemiologist familiar with most of the details. As such, the issues I raise may be considered representative of those that might be raised by other readers. 1. In the introduction, please carefully explain what Sweden’s current vaccination policies are with both varicella and zoster vaccines. Are one or two dose regimens mandated for varicella? what is the coverage rate? , What is the status of the live zoster vaccine and its coverage, specifically in Sweden? It is indicated for use in 65-year-old, but this is very different from the US where it was 60, then 50. Indeed, does dosing at 50 years affect the analyses? Does increasing coverage (what is it currently?) result in different conclusions? Is it mandated? None of this would be familiar to the reader from the manuscript as is currently written. 2. A key reference to many of the assumptions is reference 10. This cannot be looked up and is incomplete and I quote “10. Folkhälsomyndigheten. VZV vaccine - EDIT! ; 2019.”!!!!!! This model could do with a more through description than given and should be a stand-alone description that does not require this reference. Is it being, lines 62 and following regarding the model don’t always make sense to the non-expert reader? 3. Grammar corrections are needed throughout the manuscript. Just as one of many examples, lines 40-41 have 7 commas. Effective vaccines against varicella (line 39 have not been “available” since the mid-1980s but rather since the mid-1990s. 4. Line 86, varicella vaccinees are also at risk for subclinical infection and reactivation with WT zoster. This may be low. Line 99, what is meant by choosing a moderate approach to include exogenous boosting, comparable to HZ live vaccination, when the documentation for this is rather vague? This is a rather large leap of faith that may not be correct. 5. Given that Finland’s data is also used for the analyses, the programs of vaccination in that country are also important to document, particularly if they differ from that of Sweden 6. A number of the assumptions could do with strengthening from US data. For example, 116, the risk of vaccine virus being 10% seems to be rather different from the accepted US HZ data on zoster in vaccinees, which rather implies that vaccine virus is considerably rarer than 10%. Likewise, the PHN and non PHN assumptions could be substantiated better from US data. The coverage of vaccination at 95% seems to be rather high and more than seem in most countries with a mandated varicella vaccination program I do not believe the US rates are not this high, and I am certain that accurate coverage data should be available and used rather than assumptions? 7. Line 156-7 if varicella breakthrough occurs in a VZV vaccinee there is (logically) a higher rate of physician’s visits, incurring costs, no? 8. Line 174 it is not clear why an extra physician’s visit was required for the administration of the vaccine., please explain 9. As a non-expert reviewer, please explain better the concepts of sensitivity and discount rates line 212 10. The zoster vaccine is given at 65, what is the influence of giving the vaccine at age 50 as occurred in the US? Also, it is not obvious why the model does not show a reduction in zoster rates in Figure 2 in zoster vaccinees. I really tried to follow their arguments for this and it was not at all clear. It is well established from the trials that HZ incidence is reduced by HZ vaccination, why is that not seen here? Is this largely due to low vaccine coverage and partial protection rates? I would have expected a greater influence, particularly towards the end of the 100-year age spectrum. ****** 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. 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Revision 1
29 Mar 2021 Author Response Detailed response to reviwers comments Ellen Wolff November 2020 Firstly, we would like to thank the reviewers for the very good and insightful comments that add a lot to the paper. Reviewer 1: Comments to reviewer 1. 1. The authors should clearly state that zoster can be caused by the live attenuated varicella vaccine virus. This point is never clearly stated anywhere in the manuscript. Suggest 2 additional references be added at these locations. Discussion, line 301. "The number of cases of herpes zoster will never go to zero, even after universal varicella vaccination. There will always be a few cases of herpes zoster caused by reactivation of latent varicella vaccine virus. " Please cite 2 references: 1by Harpaz (2019) and by Ramachandran (2020). Discussion, lines 417-8. "There will always be a low background of herpes zoster in Sweden from reactivation of latent varicella vaccine virus in immunized citizens." Cite same 2 references. Reply: Thank you for this comment. It has now been added together with the references to the manuscript. See the discussion-section, paragraph 2, and the last paragraph. Reviewer 2: In the report by Wolff et al submitted to PLOS One a predictive study is presented from a number of assumptions that models the cost effectiveness of varicella and HZ vaccination in Sweden, using a rather not well explained or fully documented dynamic transition model. Based on the assumptions and modeling the authors conclude that the varicella vaccination program has a much stronger cost effectiveness, when given with or without the live zoster vaccination program. The live zoster vaccination program seems to only have a mild effect on incidence and cost effectiveness that leads them to conclude it is not cost effective. This is different from most of the cost effectiveness studies from other countries, which generally indicate a zoster vaccine would be cost effective. This review is given by a person knowledgeable in the field of varicella and zoster who is not a statistical epidemiologist familiar with most of the details. As such, the issues I raise may be considered representative of those that might be raised by other readers. Comment to Reviewer 2 1. In the introduction, please carefully explain what Sweden’s current vaccination policies are with both varicella and zoster vaccines. Are one or two dose regimens mandated for varicella? what is the coverage rate? , What is the status of the live zoster vaccine and its coverage, specifically in Sweden? It is indicated for use in 65-year-old, but this is very different from the US where it was 60, then 50. Indeed, does dosing at 50 years affect the analyses? Does increasing coverage (what is it currently?) result in different conclusions? Is it mandated? None of this would be familiar to the reader from the manuscript as is currently written Reply: Thank you for this comment, it is now clearly stated in the introduction that neither varicella not herpes zoster is part of a national vaccination programme in Sweden but that doses are available on the private market, see the introduction section, the last paragraph. 2. A key reference to many of the assumptions is reference 10. This cannot be looked up and is incomplete and I quote “10. Folkhälsomyndigheten. VZV vaccine - EDIT! ; 2019.”!!!!!! This model could do with a more through description than given and should be a stand-alone description that does not require this reference. Is it being, lines 62 and following regarding the model don’t always make sense to the non-expert reader? Reply: Unfortunately, the paper we would have preferred to cite in not yet published. Therefore, we have added a more thorough description of the epidemiological model. See ”The Epidemiological Model”-section. 3. Grammar corrections are needed throughout the manuscript. Just as one of many examples, lines 40-41 have 7 commas. Effective vaccines against varicella (line 39 have not been “available” since the mid-1980s but rather since the mid-1990s. Reply: We have revised the manuscript and corrected grammar mistakes. Changes have been made throughout the manuscript. We also changed the sentence to “Effective vaccines against varicella have been in use since the mid-1990s...” Thank you for noticing this. 4. Line 86, varicella vaccinees are also at risk for subclinical infection and reactivation with WT zoster. This may be low. Line 99, what is meant by choosing a moderate approach to include exogenous boosting, comparable to HZ live vaccination, when the documentation for this is rather vague? This is a rather large leap of faith that may not be correct. Reply: Thank you, this has been added to the manuscript, see section “The Epidemilogical Model”, the last paragraph, and was also accounted for in the model. 5. Given that Finland’s data is also used for the analyses, the programs of vaccination in that country are also important to document, particularly if they differ from that of Sweden Reply: This is a very important point and information has now been added to the manuscript, see “Incidence of varicella”-section. 6. A number of the assumptions could do with strengthening from US data. For example, 116, the risk of vaccine virus being 10% seems to be rather different from the accepted US HZ data on zoster in vaccinees, which rather implies that vaccine virus is considerably rarer than 10%. Likewise, the PHN and non PHN assumptions could be substantiated better from US data. The coverage of vaccination at 95% seems to be rather high and more than seem in most countries with a mandated varicella vaccination program I do not believe the US rates are not this high, and I am certain that accurate coverage data should be available and used rather than assumptions? Reply: We have added references to the manuscript to strengthen our assumptions. Varicella vaccination would be part of the national vaccination programme for children in Sweden. The programme has a coverage rate of about 98% among 2-year olds even though it is not a mandatory programme. Therefore, we believe that reaching a 95% coverage rate is reasonable. We have also included a sensitivity analysis with a coverage of 85%. 7. Line 156-7 if varicella breakthrough occurs in a VZV vaccinee there is (logically) a higher rate of physician’s visits, incurring costs, no? Reply: For patients with breakthrough varicella we did not assume that they would be hospitalized, but physician’s visits are included in the analyses. No changes have been made to the model, but the cost-section has been updated and clarified. 8. Line 174 it is not clear why an extra physician’s visit was required for the administration of the vaccine., please explain Reply: This has been clarified in the manuscript; see the resource use-section, the fourth paragraph. As of today, there is no vaccination programme in Sweden targeting people over 65 years old, for instance for seasonal influenza. Therefore, there is no natural reason to visit a physician and get the herpes zoster vaccine without needing an extra visit for the vast majority. 9. As a non-expert reviewer, please explain better the concepts of sensitivity and discount rates line 212. Reply: This has been clarified in the manuscript, see the sensitivity analyses-section, the first paragraph. 10. The zoster vaccine is given at 65, what is the influence of giving the vaccine at age 50 as occurred in the US? Also, it is not obvious why the model does not show a reduction in zoster rates in Figure 2 in zoster vaccinees. I really tried to follow their arguments for this and it was not at all clear. It is well established from the trials that HZ incidence is reduced by HZ vaccination, why is that not seen here? Is this largely due to low vaccine coverage and partial protection rates? I would have expected a greater influence, particularly towards the end of the 100-year age spectrum. Reply: We chose to model the ages where vaccination potentially has the greatest effect. Due to the incidence increasing with age and the short duration of the vaccine. We modelled vaccination at 65 years and run a sensitivity analysis for vaccination at 75 years. We found that vaccination at 75 years was the most cost-effecktive, biut neither this programme was dominant. Also, it is not realistic that a vaccination programme against herpes zoster would target 50-year-olds in Sweden and the expected effect would be lower. Figure 3 that shows the herpes zoster incidence with different vaccination strategies, has been updated to more clearly show the effects of vaccination. The small decrease in incidence is partly due to the short duration of the vaccine, vaccination coverage, and effect of the vaccine. The main reason for the modest impact is that we do not show the impact on the vaccinated cohort, but rather the impact on the zoster incidence in the entire population. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0251644.r002
7 Apr 2021 Decision Letter - Georges M.G.M. Verjans, Editor PONE-D-20-26903R1 Cost-effectiveness of varicella and herpes zoster vaccination in Sweden: an economic evaluation using a dynamic transmission model PLOS ONE Dear Dr. Wolff, 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 April 2th 2021. 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. Please include the following items when submitting your revised manuscript: 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: http://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, Georges M.G.M. Verjans, MSc, PhD Academic Editor PLOS ONE Additional Editor Comments (if provided): The authors submitted a revised manuscript (one clean and one with track changes) and their response to reviewers' comments. Before considering this revised manuscript, this Editor appreciates the authors to take care of two critical issues: 1. Manuscripts with track changes are very difficult to interpret. It is appreciated to receive a 'marked copy of the manuscript' in which the changes are indicated in 'red'. This needs to be accompanied with an updated authors' response to reviewers' comments with detailed info which text is changed, including reference to 'line numbers'. 2. Furthermore, changes to authorship have been made. This is a MAJOR ISSUE that needs to be clarified and approved by the editorial office. To request such change, this Editor appreciates to receive the following from the corresponding author: (a) the reason for the change in author list and (b) written confirmation (e-mail, letter) from all authors that they agree with the author rearrangement. [Note: HTML markup is below. Please do not edit.] [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.0251644.r003
Revision 2
28 Apr 2021 Author Response aA detailed response to reviewers comments Ellen Wolff November 2020 Firstly, we would like to thank the reviewers for the very good and insightful comments that add a lot to the paper. References to line numbers consider the version of the manuscript named “marked copy”, Reviewer 1: Comments to reviewer 1. 1. The authors should clearly state that zoster can be caused by the live attenuated varicella vaccine virus. This point is never clearly stated anywhere in the manuscript. Suggest 2 additional references be added at these locations. Discussion, line 301. "The number of cases of herpes zoster will never go to zero, even after universal varicella vaccination. There will always be a few cases of herpes zoster caused by reactivation of latent varicella vaccine virus. " Please cite 2 references: 1by Harpaz (2019) and by Ramachandran (2020). Discussion, lines 417-8. "There will always be a low background of herpes zoster in Sweden from reactivation of latent varicella vaccine virus in immunized citizens." Cite same 2 references. Reply: Thank you for this comment. It has now been added together with the references to the manuscript. See the discussion-section, lines 383-386, and 499-501 Reviewer 2: In the report by Wolff et al submitted to PLOS One a predictive study is presented from a number of assumptions that models the cost effectiveness of varicella and HZ vaccination in Sweden, using a rather not well explained or fully documented dynamic transition model. Based on the assumptions and modeling the authors conclude that the varicella vaccination program has a much stronger cost effectiveness, when given with or without the live zoster vaccination program. The live zoster vaccination program seems to only have a mild effect on incidence and cost effectiveness that leads them to conclude it is not cost effective. This is different from most of the cost effectiveness studies from other countries, which generally indicate a zoster vaccine would be cost effective. This review is given by a person knowledgeable in the field of varicella and zoster who is not a statistical epidemiologist familiar with most of the details. As such, the issues I raise may be considered representative of those that might be raised by other readers. Comment to Reviewer 2 1. In the introduction, please carefully explain what Sweden’s current vaccination policies are with both varicella and zoster vaccines. Are one or two dose regimens mandated for varicella? what is the coverage rate? , What is the status of the live zoster vaccine and its coverage, specifically in Sweden? It is indicated for use in 65-year-old, but this is very different from the US where it was 60, then 50. Indeed, does dosing at 50 years affect the analyses? Does increasing coverage (what is it currently?) result in different conclusions? Is it mandated? None of this would be familiar to the reader from the manuscript as is currently written Reply: Thank you for this comment, it is now clearly stated in the introduction that neither varicella not herpes zoster is part of a national vaccination programme in Sweden but that doses are available on the private market, see the introduction section, lines 87-89. 2. A key reference to many of the assumptions is reference 10. This cannot be looked up and is incomplete and I quote “10. Folkhälsomyndigheten. VZV vaccine - EDIT! ; 2019.”!!!!!! This model could do with a more through description than given and should be a stand-alone description that does not require this reference. Is it being, lines 62 and following regarding the model don’t always make sense to the non-expert reader? Reply: Unfortunately, the paper we would have preferred to cite is not yet published. Therefore, we have added a more thorough description of the epidemiological model. See ”The Epidemiological Model”-section, line 106-110, 114-118, and 140-141. 3. Grammar corrections are needed throughout the manuscript. Just as one of many examples, lines 40-41 have 7 commas. Effective vaccines against varicella (line 39 have not been “available” since the mid-1980s but rather since the mid-1990s. Reply: We have revised the manuscript and corrected grammar mistakes. Changes have been made throughout the manuscript. We also changed the sentence to “Effective vaccines against varicella have been in use since the mid-1990s...” Thank you for noticing this. 4. Line 86, varicella vaccinees are also at risk for subclinical infection and reactivation with WT zoster. This may be low. Line 99, what is meant by choosing a moderate approach to include exogenous boosting, comparable to HZ live vaccination, when the documentation for this is rather vague? This is a rather large leap of faith that may not be correct. Reply: Thank you, this has been added to the manuscript, see section “The Epidemiological Model”, the last paragraph, lines 140-141, 144-146. 5. Given that Finland’s data is also used for the analyses, the programs of vaccination in that country are also important to document, particularly if they differ from that of Sweden Reply: This is a very important point and information has now been added to the manuscript, see “Incidence of varicella”-section, lines 150-151. 6. A number of the assumptions could do with strengthening from US data. For example, 116, the risk of vaccine virus being 10% seems to be rather different from the accepted US HZ data on zoster in vaccinees, which rather implies that vaccine virus is considerably rarer than 10%. Likewise, the PHN and non PHN assumptions could be substantiated better from US data. The coverage of vaccination at 95% seems to be rather high and more than seem in most countries with a mandated varicella vaccination program I do not believe the US rates are not this high, and I am certain that accurate coverage data should be available and used rather than assumptions? Reply: We have added references to the manuscript to strengthen our assumptions. Varicella vaccination would be part of the national vaccination programme for children in Sweden. The programme has a coverage rate of about 98% among 2-year olds even though it is not a mandatory programme. Therefore, we believe that reaching a 95% coverage rate is reasonable. We have also included a sensitivity analysis with a coverage of 85%. 7. Line 156-7 if varicella breakthrough occurs in a VZV vaccinee there is (logically) a higher rate of physician’s visits, incurring costs, no? Reply: For patients with breakthrough varicella we did not assume that they would be hospitalized, but physician’s visits are included in the analyses. No changes have been made to the model, but the cost section has been updated and clarified. 8. Line 174 it is not clear why an extra physician’s visit was required for the administration of the vaccine., please explain Reply: This has been clarified in the manuscript; see the resource use-section, line 218-220. As of today, there is no vaccination programme in Sweden targeting people over 65 years old, for instance for seasonal influenza. Therefore, there is no natural reason to visit a physician and get the herpes zoster vaccine without needing an extra visit for the vast majority. 9. As a non-expert reviewer, please explain better the concepts of sensitivity and discount rates line 212. Reply: This has been clarified in the manuscript, see the sensitivity analyses section, lines 277-280. 10. The zoster vaccine is given at 65, what is the influence of giving the vaccine at age 50 as occurred in the US? Also, it is not obvious why the model does not show a reduction in zoster rates in Figure 2 in zoster vaccinees. I really tried to follow their arguments for this and it was not at all clear. It is well established from the trials that HZ incidence is reduced by HZ vaccination, why is that not seen here? Is this largely due to low vaccine coverage and partial protection rates? I would have expected a greater influence, particularly towards the end of the 100-year age spectrum. Reply: We chose to model the ages where vaccination potentially has the greatest effect. Due to the incidence increasing with age and the short duration of the vaccine. We modeled vaccination at 65 years and run a sensitivity analysis for vaccination at 75 years. We found that vaccination at 75 years was the most cost-effective, but the programme was dominant. Also, it is not realistic that a vaccination programme against herpes zoster would target 50-year-olds in Sweden and the expected effect would be lower. Figure 3, which shows the herpes zoster incidence with different vaccination strategies, has been updated to more clearly show the effects of vaccination. The small decrease in incidence is partly due to the short duration of the vaccine, vaccination coverage, and effect of the vaccine. The main reason for the modest impact is that we do not show the impact on the vaccinated cohort, but rather the impact on the zoster incidence in the entire population. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0251644.r004
30 Apr 2021 Decision Letter - Georges M.G.M. Verjans, Editor Cost-effectiveness of varicella and herpes zoster vaccination in Sweden: an economic evaluation using a dynamic transmission model PONE-D-20-26903R2 Dear Dr. Wolff, 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, Georges M.G.M. Verjans, MSc, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Authors revised the manuscript satisfactory by addressing the reviewers' critiques sufficiently. Reviewers' comments: Not applicable. https://doi.org/10.1371/journal.pone.0251644.r005
Formally Accepted
4 May 2021 Acceptance Letter - Georges M.G.M. Verjans, Editor PONE-D-20-26903R2 Cost-effectiveness of varicella and herpes zoster vaccination in Sweden: an economic evaluation using a dynamic transmission model Dear Dr. Wolff: 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 Prof. Dr. Georges M.G.M. Verjans Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0251644.r006

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