Proposed Conceptual and Experience-Based Framework for Reaching an Optimal Vaccine Launch Strategy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript proposes the Vaccine Launching Value Project (VLVP) framework for vaccine launch. The topic is of significance in public health and health economics, and the overall structure is complete. However, the manuscript has notable weaknesses in innovation, methodological clarity, case support, and academic rigor, requiring substantial revisions.

(1) Although VLVP, Brocoli, Cauliflower, and Tomato are self-created concepts, they are not compared with existing vaccine launch frameworks or HTA methods, so the theoretical contribution and incremental value cannot be demonstrated.

(2) The methodological description is seriously insufficient. The study design, data sources, model structure, and decision criteria are not clearly explained. The statement “15 years and 10 vaccines” is only descriptive background, with no empirical process or validation provided.

(3) The manuscript only uses rotavirus vaccine as a single case, which relies mainly on qualitative description. There are no quantitative results, comparative analyses, or cost-effectiveness data, which weakens the persuasiveness of the arguments.

(4) The authors fail to provide evidence that the VLVP framework can actually improve vaccination coverage, reduce costs, improve decision-making, or accelerate market access. The conclusions lack empirical support.

(5) The manuscript takes a strong industry perspective, but the authors do not clarify any potential relationships with vaccine manufacturers or relevant industries. A clear conflict-of-interest statement is strongly recommended.

(6) The logical connections among “value assessment → stakeholder analysis → implementation strategy” are loose and unclear. The synergies and practical operational pathways among these components are not explained.

(7) The literature support for key methods and models is inadequate. Some citations are weakly related to the arguments, and the reference format is inconsistent.

(8) There is excessive repetition, overly lengthy paragraphs, and high overlap between the abstract and conclusion. It is recommended to condense the text and strengthen the novelty of the conclusions.

(9) The English writing throughout the manuscript needs major revision, with obvious non-native or AI-generated phrasing, grammatical issues, and inappropriate academic expressions.

Author Response

This manuscript proposes the Vaccine Launching Value Project (VLVP) framework for vaccine launch. The topic is of significance in public health and health economics, and the overall structure is complete. However, the manuscript has notable weaknesses in innovation, methodological clarity, case support, and academic rigor, requiring substantial revisions.

Response: Thank you for this general and useful comment. We hope we have responded well to the criticisms made. The focus of the first reviewer seems to be on a comparative evaluation between the VLVP and existing methods of launching new vaccines. That was not the intention of this paper. We have had the chance to explore and investigate many different approaches to measuring value outside the conventional HTA approach on many new vaccines over a period of 20 years. When those exercises were conducted, there was no plan, program, or structure in place to describe comprehensive value measurement outside HTA. The aim of this article is to present a structure, a plan and a program to globalize vaccine value measurement. The starting point for moving beyond conventional HTA was that a vaccine producer, when launching a new vaccine, may have additional operational objectives beyond obtaining reimbursement. To make a reasonable profit in vaccine production it also requires considering volume, demonstrating sufficient effectiveness to support long-term use, and enhancing the production process. To optimize volume requires reaching the many different stakeholders who may be directly or indirectly interested in the vaccine and evaluating from their value perspective. Long-term success in disease control requires introducing the vaccine in the best way to maintain the effect. The article covers three critical points:

-Complexity of the launch process, not limited to obtaining EMA approval and reimbursement;

-The many different value aspects to assess from the perspectives of many different stakeholders;

-Designing the initial implementation of the vaccine program to optimize long-term effect, with a monitoring program to measure success.

 

(1) Although VLVP, Brocoli, Cauliflower, and Tomato are self-created concepts, they are not compared with existing vaccine launch frameworks or HTA methods, so the theoretical contribution and incremental value cannot be demonstrated.

Response: We understand the comment and it is an interesting view. However, it was not our intention to make a formal comparison with existing launch methods for economic investigation of vaccines using HTA for health authorities. The intention was rather to demonstrate that successful launch of a new vaccine to maximizes the chance of long-term success is a complex undertaking. An extended view of the value of vaccines has been developed by manufacturers over the last 20 years or so, aiming to increase market access for new vaccines. When this search for new approaches began, it typically used opportunistic study designs that demonstrated and measured value aspects that were not conventionally reported in HTA.

The paper presents a more structured and systematic approach for the economic value assessment of a new vaccine with a focus on long-term success. Our hands-on experience of the launch of 10 new vaccines over a comparatively short period, not all of which had easy launches, provided us with a unique opportunity to review the evolution of new approaches and to consolidate them into a systematic framework.  This is the aim of the paper.

(2) the methodological description is seriously insufficient. The study design, data sources, model structure, and decision criteria are not clearly explained. The statement “15 years and 10 vaccines” is only descriptive background, with no empirical process or validation provided.

Response: Thank you for this helpful comment. The purpose of this paper is to present a summary of the many uncoordinated initiatives that have been developed to measure specific aspects of value for new vaccines. At the beginning of this process there was no structure and no precise view of how best to evaluate the full value of a vaccine. Many ideas were explored, but as it was a new area and the knowledge was limited, there was no structured program. Naturally the industry followed the conventional and requested approach of cost-effectiveness analysis (CEA), but we were convinced that vaccines had more value than it could be shown by a CEA embedded in HTA. It was not our intention in this paper to present details of methods used to investigate areas such as ‘quality of care’, ‘cost-preference for co-payment’ of a vaccine by working mothers, or ‘reduction in work absenteeism’ after the introduction of the vaccine. These details are presented in the publications describing each investigation that are referenced in the article. Our intention was to provide a summary of the various ideas developed, synthesized into a structured approach, as a helpful guide for persons interested in the subject. The paper’s original structure with Methods and Results sections may have caused confusion over the article’s purpose, and we have restructured the paper to address this.

(3) The manuscript only uses rotavirus vaccine as a single case, which relies mainly on qualitative description. There are no quantitative results, comparative analyses, or cost-effectiveness data, which weakens the persuasiveness of the arguments.

Response: It was not our intention to quantify the gains made in different domains for the different vaccines. The cited references describe the value assessments conducted. The intention of this paper was to provide an overview of the ideas explored and developed, so that readers understand in broad terms how to identify stakeholders and the extended benefits relevant to each other. Some of the new evaluations were instructive not only for NITAGs in Europe, but also in middle- and low-income countries at global level. These approaches were introduced through a Taskforce of ISPOR on the economic value of Vaccines in 2018. Later assessment found these new approaches were helpful in real life, as mentioned in a publication by J Mauskopf et al in 2022 (Value Health, 2022, 25 (5), 810-823..

The rotavirus vaccine is frequently mentioned because it acted as a perfect ‘laboratory condition’ for studying the impact of initial implementation on long-term vaccine effect. Due to a known side effect of rotavirus vaccine (intussusception) associated with vaccine administration at the age of 1 year, only young infants could be vaccinated and there was no option for vaccine catch-up. This allowed us to investigate the effect of decisions made at the start of implementing a vaccine program on the long-term vaccine effect, which we studied in the RotaBIS study over 15 years of follow-up. The most interesting results on rotavirus vaccine effect were found in Europe because of the wide range of approaches to the introduction of rotavirus vaccination. UK, Finland, Spain, Austria, Belgium, Italy, and the Nordic countries gave a nice panoply of different launches of the vaccine that demonstrated different long-term effects and in effect provided a series of natural experiments.

Rotavirus was also a difficult vaccine to launch in Europe, because rotavirus and its consequences were perceived as minor. The difficulties of launching the rotavirus vaccine in Europe, despite impressive effect data from clinical trials, was the main driver for developing the idea of many different aspects of value for different stakeholders. For example, the improvement of hospital quality of care resulting from the fall in rotavirus-related hospitalizations was relevant to hospital managers, and the reduction of work absenteeism was relevant to employers and working parents. These are examples of benefits that would not be covered by conventional HTA investigation, but which were useful in the support and positioning of the vaccine. They illustrate the principle of investigating broader vaccine effects relevant to different stakeholders, but it was not our intention to provide a quantitative list. As noted above, the paper’s original structure with Methods and Results sections may have caused confusion over the article’s purpose, and we have restructured the paper to address this.

(4) The authors fail to provide evidence that the VLVP framework can actually improve vaccination coverage, reduce costs, improve decision-making, or accelerate market access. The conclusions lack empirical support.

Response: Thank you for this comment, As noted above, it was not our intention to compare the VLVP versus existing methods of launching new vaccines. It is a very valid question. However, the VLVP should not be seen as a method to replace or to be incorporated into HTA; it should rather be seen as an approach to extend the value assessment of a new vaccine and support its optimal positioning. We have been invited to demonstrate and explain the extra value gain of the rotavirus vaccine to many different authorities and congresses across the world (87 countries worldwide). When making presentations, we were able to illustrate the extended benefits alongside clinical gain and CE, and were often asked at the end of the presentation why authorities were hesitant in approval. At the time, there was no comprehensive program for extended value assessment, and most of the time we could therefore present only a partial picture. The VLVP was developed to provide a systematic framework to help guide assessment of the extended value of vaccines. We have restructured and rewritten the paper to try to make this clearer.

(5) The manuscript takes a strong industry perspective, but the authors do not clarify any potential relationships with vaccine manufacturers or relevant industries. A clear conflict-of-interest statement is strongly recommended.

Response: Thank you for this comment. BS was employed for many years in the pharmaceutical industry and the synthesis presented in the article draws on his extensive industry experience. However, the development of the VLVP is an initiative taken five years after leaving the industry. MR is a pediatrician. He was not directly involved with the launching work developed, but he gave major support for the monitoring of the vaccine effect in the RotaBIS study.

The publications on the Tomato Tool were all developed without industry support. The Brocoli plan was presented as such in the European IMI (Innovative Medicines Initiative) program of VITAL (Vaccines and Infectious Diseases in the Ageing population), but it was never presented to the external world. Only the Cauliflower was an initiative taken during industry employment, and it was formally published (JMA&HP, 2017, 5(1): 1336044) before the flower concept was developed by an ISPOR Taskforce on Value measurement in the US (Value Health 2018, 21 (2), 119-123).

(6) The logical connections among “value assessment → stakeholder analysis → implementation strategy” are loose and unclear. The synergies and practical operational pathways among these components are not explained.

Response: Thank you for this helpful comment. We have restructured and rewritten the text to try to be more explicit on this point. The first step in creating a compelling economic story about a new vaccine is to develop an extended framework to help identify specific items to investigate and the links between them. This is the purpose of the Brocoli plan, which is a comprehensive toolbox listing different domains for consideration. The Cauliflower Method was originally developed before the Brocoli plan, because it was a response to the difficulties encountered in launching the rotavirus vaccine in Europe. At that time we were focused only on identifying evidence that authorities wanted to see: i.e. assessment of cost-effectiveness with a budget impact analysis. This work resulted in developing the list of stakeholders (the 6 Ps) and the aspects of value relevant to each. Although the Cauliflower Method was the first of the tools in this paper to be developed, when synthesizing them into the VLVP we considered that it would be better to use a more systematic approach, using the Brocoli Plan first to design the overall framework and then moving on to specifics using the Cauliflower and the Artichoke. The Artichoke considers new economic assessment methods relevant for different stakeholders. The Tomato is the most recent of our tools to be developed, because multiple years of observation were required to measure long-term vaccine effect in the real world. Now that we have constructed the Tomato Tool, it can be used before the launch of a new vaccine to model potential scenarios for how the short- and long-term vaccine effect may be affected by elements of disease epidemiology and characteristics of the vaccine implementation. The Tomato Tool can thus be considered the most important component in the VLVP scheme. We have extensively rewritten the paper to try to make these connections clearer.

(7) The literature support for key methods and models is inadequate. Some citations are weakly related to the arguments, and the reference format is inconsistent.

Response: Many thanks for this comment. We were too hasty here. We have now verified all the literature and adjusted where necessary. As noted above, we did not conduct a comparative evaluation with other methods because that was not the objective of this paper.

(8) There is excessive repetition, overly lengthy paragraphs, and high overlap between the abstract and conclusion. It is recommended to condense the text and strengthen the novelty of the conclusions.

Response: We have restructured and rewritten the text to try to be more concise and avoid overlap where possible.

(9) The English writing throughout the manuscript needs major revision, with obvious non-native or AI-generated phrasing, grammatical issues, and inappropriate academic expressions.

Response: We have now worked with a native English speaker to adjust the language of the manuscript. We did not use AI.

Reviewer 2 Report

Comments and Suggestions for Authors

The topic developed by the authors is very interesting. They present a structured protocol for launching new vaccines. The paper is well-written, but it is designed in a traditional structure with sections for introduction, methods, results, discussion, and conclusions. However, in my opinion, it would be more appropriate to present it in a free-flowing format with different headings.
The paper should be reviewed and improved in some sections.
The abstract needs improvement. For example, the background is very brief, and the objectives are not clearly stated. The keywords should be reviewed.
The paper is repetitive at times.
The Vaccine Launching Value Project (VLVP) and the different evaluation plans are well explained. However, in the discussion, the authors refer to the multidimensional concept of value, which goes far beyond health benefits, and they do so from a general perspective. In fact, they refer to public health as a squid, given the diversity of its possible tentacles. This diversity of elements and variables may make it difficult to extrapolate these procedures to different contexts. This aspect should be expanded upon by the authors in the discussion and conclusions sections.
A limitations section should also be included.
The references section needs to be reviewed. I'll give just a few examples. Reference 1 should be clarified. Reference 18 is not properly referenced. In other words, the references need to be reviewed. References 22, 27, 29, etc.

Author Response

The topic developed by the authors is very interesting. They present a structured protocol for launching new vaccines. The paper is well-written, but it is designed in a traditional structure with sections for introduction, methods, results, discussion, and conclusions.

However, in my opinion, it would be more appropriate to present it in a free-flowing format with different headings.
Thank you for this general comment. We agree that the article does not fit readily into a traditional format. As noted above in responses to the comments of the first reviewer, use of the traditional format may have been confusing, as it may have set up expectations of a comparative assessment of different methods of launching a new vaccine, which was not the objective of the paper. We have therefore restructured and rewritten the paper into a new format with different headings, which we hope is clearer and more appropriate to the content.

The paper should be reviewed and improved in some sections.
The abstract needs improvement. For example, the background is very brief, and the objectives are not clearly stated.

Thank you for this comment. We have rewritten the abstract to try to be more explicit about our objectives, and also to take account of the comments made by the first reviewer.

The keywords should be reviewed.
We have reviewed and adjusted the keywords

The paper is repetitive at times.
As noted above in our response to the comments of the first reviewer, we have restructured and rewritten the text to try to be concise and to avoid overlaps and repetition where possible.

The Vaccine Launching Value Project (VLVP) and the different evaluation plans are well explained. However, in the discussion, the authors refer to the multidimensional concept of value, which goes far beyond health benefits, and they do so from a general perspective. In fact, they refer to public health as a squid, given the diversity of its possible tentacles. This diversity of elements and variables may make it difficult to extrapolate these procedures to different contexts. This aspect should be expanded upon by the authors in the discussion and conclusions sections.
Thank you for this helpful comment, this is a good point. We have rewritten the discussion and tried to explain in greater detail how investigating a specific point may lead to considering other inter-related variables in further investigation.

A limitations section should also be included.
Thank you for this helpful comment. We have added an explicit limitations section as suggested.

The references section needs to be reviewed. I'll give just a few examples. Reference 1 should be clarified. Reference 18 is not properly referenced. In other words, the references need to be reviewed. References 22, 27, 29, etc.

Thank you for this comment and we agree that the references were produced too hastily. We have now reviewed all the references to be more precise.

Reviewer 3 Report

Comments and Suggestions for Authors

This is potentially relevant paper. However, in its current form the manuscript should be reclassified as a Perspective or Opinion type of paper. The manuscript lacks key elements of original scientific research, such as a clearly defined methodology, systematic data collection, or reproducible analytical framework. Although the paper has a formal structure of an article, the “Methods” section for example primarily describes the authors’ accumulated experience from vaccine launches over 15 years, rather than a formal, transparent, and reproducible research process. Similarly, the “Results” section does not present empirical findings but instead introduce conceptual frameworks (e.g., Brocoli Plan, Cauliflower Method, Tomato Tool), which are not validated through systematic analysis or comparative evaluation. The manuscript core contribution is in proposing a conceptual and experience-based framework for vaccine launch strategy. Instead of "Optimal Strategies for Launching New Vaccines in High-Income Countries" (there is nothing optimal that would have been proven in this manuscript) the title should be "Proposed Conceptual and Experience-Based Framework for Vaccine Launch Strategies." Only then future scientific research can prove or disprove how successful such a framework could actually be. 

Comments on the Quality of English Language

Run the paper paragraph-by-paragraph through some AI instrument to refine your English. Do not use AI to create sentences and use stringent quality control to make sure AI suggestions are acceptable. 

Author Response

1. This is potentially relevant paper. However, in its current form the manuscript should be reclassified as a Perspective or Opinion type of paper. The manuscript lacks key elements of original scientific research, such as a clearly defined methodology, systematic data collection, or reproducible analytical framework. Although the paper has a formal structure of an article, the “Methods” section for example primarily describes the authors’ accumulated experience from vaccine launches over 15 years, rather than a formal, transparent, and reproducible research process. Similarly, the “Results” section does not present empirical findings but instead introduce conceptual frameworks (e.g., Brocoli Plan, Cauliflower Method, Tomato Tool), which are not validated through systematic analysis or comparative evaluation.

Response: We completely agree with this comment, also mentioned by the second reviewer. We adjusted the classification of the manuscript to ‘Opinion’. We also restructure the manuscript into a format that is more suitable for an Opinion: Introduction, Concept, Examples, Discussion, Recommendation.

2. The manuscript core contribution is in proposing a conceptual and experience-based framework for vaccine launch strategy. Instead of "Optimal Strategies for Launching New Vaccines in High-Income Countries" (there is nothing optimal that would have been proven in this manuscript) the title should be "Proposed Conceptual and Experience-Based Framework for Vaccine Launch Strategies." Only then future scientific research can prove or disprove how successful such a framework could actually be. 

Response: We understand the point that we haven’t done any formal comparative evaluation of different launch strategies of vaccines in this paper, but we have done such an evaluation in papers we mentioned by which we discovered that it is possible to go for an ‘optimal’ launch strategy with the vaccination. The last paper we published was on that focus, coming up with a success-index of vaccination long-term comparing different country data (Vaccines, 2024, 12, 1265).

Can we compromise about the title: Proposed Conceptual and Experience-Based Framework for Reaching an Optimal Vaccine Launch Strategy.

Searching for ‘optimality’ is key in this manuscript. We shouldn’t have developed a full and extended program if it was not that we were looking for optimality of the vaccination program. This is often missed when starting to launch a new vaccine program and we like with this paper to have a focus on.

 

3. Comments on the Quality of English Language

Run the paper paragraph-by-paragraph through some AI instrument to refine your English. Do not use AI to create sentences and use stringent quality control to make sure AI suggestions are acceptable. 

Response: We now engaged the medical writer we are most familiar with to work on this new version. She supported us in previous publications, which was not the case in this first submission due to time constraints. I am most grateful to her as she knows best how I’m thinking and reflecting in my wording that is not using ‘optimal’ English. I hope that this new version goes for optimality in the correct language use.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

none

Reviewer 2 Report

Comments and Suggestions for Authors

The paper has been improved following the recommendations and can be published in present form.

Reviewer 3 Report

Comments and Suggestions for Authors

I have no further comments.

Comments on the Quality of English Language

Run the paper paragraph-by-paragraph through some AI instrument to refine your English. Do not use AI to create sentences and use stringent quality control to make sure AI suggestions are acceptable.