PONE-D-24-13297Health impact and cost-effectiveness analysis of gender-neutral versus female-only 9-valent human papillomavirus vaccination in TaiwanPLOS ONE

Dear Dr. Sukarom,

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.

The main limitation of the report is that the model used in the study assumes a lifelong duration of vaccine protection and herd immunity which may be unrealistic and unsubstantiated by available data. This assumption potentially overestimates the long-term benefits of vaccination if vaccine-induced immunity wanes over time or if coverage rates fall below expectations.

Authors are invited to comment convincingly on the long time horizon of 100 years which introduces uncertainty due to potential changes in healthcare policies, and screening programmes over time, which are not accounted for in the model. For example, the model is completely silent about emerging evidence on the 10-year effectiveness of single-dose HPV vaccination and the potential implications for vaccination programmes.

From a research ethics perspective, and in line with Journal policy, authors need to do more to enhance the reproducibility of their findings (eg. Through open-access disclosure of data files) and generalizability to other settings (eg. Currencies, vaccine coverage flexibility in line with WHO cervical cancer elimination agenda). This follows logically from the observation that while the model is adapted to the Taiwanese setting, using Taiwan-specific data for disease incidence and mortality, certain inputs are based on studies from other countries.

Please submit your revised manuscript by Oct 31 2024 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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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.

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We look forward to receiving your revised manuscript.

Kind regards,

Emmanuel Timmy Donkoh, PhD

Academic Editor

PLOS ONE

Journal Requirements:

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2. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

https://pubmed.ncbi.nlm.nih.gov/37183965/

https://linkinghub.elsevier.com/retrieve/pii/S2212109922001315

https://www.eurogin.com/content/dam/markets/aest/eurogin/pdfs/2022/2022-Abstracts-MCP.pdf

https://pubmed.ncbi.nlm.nih.gov/37183965/

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

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5.  Thank you for stating the following financial disclosure: “This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA”

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.

6. Thank you for stating the following in the Competing Interests section: “I have read the journal's policy and the authors of this manuscript have the following competing interests:

Hung-Hsueh Chou received honorarium for lectures/presentations/educational events from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Takeda Pharmaceuticals, and AstraZeneca

Pen-Yuan Chu has no conflict of interest to report.

Ying-hui Wu and Casey Feng are employees of MSD Taiwan, Taipei, Taiwan.

Isaya Sukarom is an employee of MSD Thailand, Bangkok, Thailand.

Wei Wang and Andrew Pavelyev are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA at the time of the study.”

We note that one or more of the authors are employed by a commercial company: MSD Taiwan, MSD Thailand and Merck Sharp & Dohme LLC

a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form. Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.” If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

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Additional Editor Comments:

The main limitation of the report is that the model used in the study assumes a lifelong duration of vaccine protection and herd immunity which may be unrealistic and unsubstantiated by available data. This assumption potentially overestimates the long-term benefits of vaccination if vaccine-induced immunity wanes over time or if coverage rates fall below expectations.

Authors are invited to comment convincingly on the long time horizon of 100 years which introduces uncertainty due to potential changes in healthcare policies, and screening programmes over time, which are not accounted for in the model. For example the model is completely silent about emerging evidence on the 10-year effectiveness of single-dose HPV vaccination and the potential implications for vaccination programmes.

From a research ethics perspective, and in line with Journal policy, authors need to do more to enhance the reproducibility of their findings (eg. Through open-access disclosure of data files) and generalizability to other settings (eg. Currencies, vaccine coverage flexibility in line with WHO cervical cancer elimination agenda). This follows logically from the observation that while the model is adapted to the Taiwanese setting, using Taiwan-specific data for disease incidence and mortality, certain inputs are based on studies from other countries.

[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: No

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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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

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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

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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 study aims to assess the health and economic impact and cost-effectiveness of implementing gender-neutral vaccination (GNV) with the 9vHPV vaccine in Taiwan. The manuscript, however, lacks some important information in the main text. Here are some points I would like the authors to consider to further highlight the contribution of the study.

1. What is your perspective on this economic evaluation study? I couldn't find it in the text.

2. What is the baseline year? Is it 2017?

3. What is the natural history of HPV in your dynamic transmission model? Please provide a diagram as Figure 1.

4. Could you please conduct both deterministic and probabilistic sensitivity analyses for your model?

5. Why did you set the time horizon to 100 years? Typically, the time horizon is set to match the average life expectancy.

6. Could you please combine Table 1 and Table 2? I don't think it is necessary to separate them.

7. This study is well worth discussing. While HPV brings limited benefits to the male population, it incurs significant costs. Please explain in the discussion section how the 9vHPV GNV strategy compares economically with other vaccine programs (e.g., hepatitis B and measles vaccines) in Taiwan.

Reviewer #2: The authors presented the analysis to estimate the impact of GNV on cervical cancer and other HPV-related diseases on both females and males. More details for adapting the model to the Taiwanese setting should be provided.

Model design

1. Lines 81-82, 89-91, 150-151, 154-156. The model used a previously developed model with adaption to the Taiwanese setting. “All parameters were initially set to the values from the US model and then adjusted to converge on the cervical cancer incidence rate and the cervical cancer mortality rate”.

More information should be provided in the Supplementary file to make the current submission a standalone study. In particular, please show the model fitting to the Taiwanese disease data and include the source of the Taiwanese disease data. Model parameters, such as progression rate, should be compared between the Taiwanese study and the original US study.

2. Lines 91-92. The attribution of specific HPV types should be presented explicitly with justification.

3. Lines 106-109. Young adults likely have more sexual partners when compared to adolescents and older adults. That is, if the mean number of sexual partners is pre-specified in each sexual activity categories, the proportion of population in the sexual activity categories should vary by age.

In Supplementary Table 1, The proportion of the sexual activity categories, with pre-specified mean number of sexual partners per year, were independent of ages. The authors please justify the assumption of this setting and explain how this affects the transmission dynamic. Sensitivity analysis that considers age-varying proportion could be provided.

4. Lines 114-115. “the percentage of females receiving gynecological cancer screening tests (88%)”. From Supplementary Table 2, the quoted percentage referred to the percentage that females received screening tests at least once in their lifetime and the screening test should be referred to cervical screening only. The proportion that females received a screening test in the past year was around 30%. Please clarify in the text.

5. Lines 128-129. The cost of vaccine itself was NTD1,880 per dose, or equivalently USD$60 per dose. This was lower than a recent Taiwanese HPV vaccination CEA study (quoted NTD2,300 per dose) (https://doi.org/10.1016/j.vhri.2022.06.006). Either price was lower than the one quoted by the Health Promotion Administration, Ministry of Health and Welfare (NTD3,000-7,000 per dose) (https://www.hpa.gov.tw/EngPages/Detail.aspx?nodeid=1752&pid=11888). The authors please justify this setting.

6. Provide the exchange rate of NTD to USD, GBP, or Euro.

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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

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PONE-D-24-13297R1Health impact and cost-effectiveness analysis of gender-neutral versus female-only 9-valent human papillomavirus vaccination in TaiwanPLOS ONE

Dear Dr. Sukarom,

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 May 01 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Emmanuel Timmy Donkoh, PhD

Academic Editor

PLOS ONE

Journal Requirements:

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.

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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

Reviewer #3: All comments have been addressed

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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

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: Yes

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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

Reviewer #3: Yes

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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: The authors have addressed the comments for the initial submission appropriately. There are some new items based on the revision of the manuscript.

1. In Table S1, the authors showed HPV attribution in different HPV-related cancers. The HPV prevalence for penile cancer was stated as 100% in the table, which is unlikely based on the reference that the authors cited. The authors please justify this setting, or revise the value and, if necessary, corresponding results. Also, as the authors said, HPV attribution in cancer cases varies by geographic location and population. Please state whether local data specific to the Taiwanese setting was used or the location that they referred to.

2. The authors presented calibration results to cancer incidence that was related to 4vHPV and 9vHPV. The authors please state whether calibration has been done to the incidence that was related to non-vaccine-targeted HPV types, and how the model handles the disease burden that is related to non-vaccine-targeted HPV types.

3. The authors calibrated the model to the age-standardized rate of cancer incidence. The age-specific incidence rate, e.g., the peak and the trend, varies by age and cancer type. The authors please state the potential impact of calibrating the model outputs to an age-standardized rate instead of an age-specific rate, e.g., this approach affects the projected incidence and so the associated costs and health benefits across time horizon.

Reviewer #3: Thank you for the opportunity to review this manuscript. It provides additional information on the optimal program structure around HPV vaccination, to hasten elimination of HPV-related diseases across the world. Since I have noted the questions from the previous set of reviews and the detailed responses from the authors, I would like to focus on a more policy/implementation perspective; a policy-level 'so what' as it were.

1. Most health systems across the world are struggling with sustainable financing, in the setting of ageing populations as well as other remerging threats. With the exception of genital warts, the health impact of on the other conditions is reduced by both fewer numbers, coupled with relatively low incidence of some of the conditions (like respiratory papillomatosis). What would be the implications for decision-makers, who have to consider many factors before investing in gender neutral HPV vaccination?

2. Most of the health impact and cost savings from averted managements costs emanate from conditions associated with HPV 6, 11, 16 and 18. Though this may not be relevant to Taiwan that already is implementing the 9vHPV, what can these finding inform policymakers, especially in LMICs, considering whether to 9vHPV in their national programs?

3. These findings are Taiwan-specific and fit into the health system realties of this setting. However, by publishing, the authors also aim to guide decision-making and policy initiatives across the world. Looking at the relative burden of various HPV-related conditions across the world, what would the authors recommend to countries oaf various economic contexts, based on the insights from their study? Focus on one-dose strategies but with high coverage among girls? Gender-neutral one-dose strategy? Girls-only two doses? While the current model did not address all these scenarios together (just compared FOV vs GNV), the authors can bring together other modelling studies published in the last few years to weave a narrative that can guide program managers and teams across the world.

4. It would also add value even to the study context, to summarize what the total cost implication would be, if Taiwan was to plan to intrude gender neutral HPV vaccine, in relation to its current health expenditure (more broadly or more specifically on vaccination). This can then be extrapolated to the investment needed to get the benefits within the time horizon specified. It is important to note that this information is already available within the CEA determinations, but for policy-level decision-making, cost implication is vital for planning.

5. As part of the responses to a previous review, the authors stated that since Taiwan is not considering a single-done program, there was no need to mention it in their discussion, a position I disagree with. We publish to share our findings, put them in context, and also discuss their generalizability and implications to global audiences. It would value for this study to contribute to the discussion that many countries are having around gender neutral, extended catch-up vaccination, one-dose strategies, etc.

My points above are made with the understanding that some of these points may not have been addressed by the current model, but nevertheless warrant being part of the discussion and recommendation.

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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

Reviewer #3: Yes: Valerian Mwenda

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[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.

Health impact and cost-effectiveness analysis of gender-neutral versus female-only 9-valent human papillomavirus vaccination in Taiwan

PONE-D-24-13297R2

Dear Dr. Sukarom,

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.

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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,

Emmanuel Timmy Donkoh, PhD

Academic Editor

PLOS ONE

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

Reviewer #3: All comments have been addressed

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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

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

Reviewer #3: Yes

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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: The authors have addressed the comments in the previous round of review.

Reviewer #3: I feel the authors' responses are adequate and satisfactory and have made the required revisions on the manuscript.

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Reviewer #2: No

Reviewer #3: Yes: Valerian Mwenda

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