Global Health Preparedness Frameworks and Recombinant Vaccine Platforms: A Public Health Perspective on Regulations and System Readiness

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The topic of this review is timely and critical, however, in its current form, the title of the review doesn't align with the actual content. The title promised an analysis of "Recombinant Vaccine Platforms", yet the text was mainly about the public health preparedness systems and policy (e.g., general overviews of US/EU frameworks) that are not specific to recombinant technology. 
Major points:
1. The current text spends too much energy describing the existence of preparedness frameworks rather than analyzing how recombinant platforms specifically interact within these frameworks. I would suggest condense the general introduction of public health systems into a concise background section, and thoroughly discuss the specific "Actions" listed in Table 3.
2. Most of the current discussion is based on COVID-19 pandemic, while recombinant technology did not start in 2019. By ignoring pre-COVID history, the current review is more like a retrospective on a single event rather than a forward-looking review of the technology. It would be highly beneficial to include examples of recombinant platforms applied to other disease, such as Ebola, influenza, HPV, etc. Including such examples would validate the authors' claims about recombinant platforms beyond the emergency use of 2020-2022.
3. The manuscript only lists "Actions" theoretically in Table 3, but lacks of concrete action examples in real-world, such as how did the specific mechanisms (e.g., rolling reviews, emergency use authorization criteria for mRNA vs. protein subunits) utilized by agencies like the FDA or EMA. Such discussion will help transforming the manuscript from a general policy overview to a specific, mechanism-driven analysis of the technology's role in public health.

Author Response

Reviewer 1

Comments and Suggestions for Authors

 

The topic of this review is timely and critical, however, in its current form, the title of the review doesn't align with the actual content. The title promised an analysis of "Recombinant Vaccine Platforms", yet the text was mainly about the public health preparedness systems and policy (e.g., general overviews of US/EU frameworks) that are not specific to recombinant technology.

 

R: Thank you for your comment. We have revised the title of the manuscript to better align it with the scope and focus of the review, emphasizing the role of recombinant vaccine platforms within public health preparedness frameworks.

 

Global Health Preparedness Frameworks and Recombinant Vaccine Platforms: A public health perspective on Regulations and System Readiness

 

Major points:

1- The current text spends too much energy describing the existence of preparedness frameworks rather than analyzing how recombinant platforms specifically interact within these frameworks. I would suggest condense the general introduction of public health systems into a concise background section, and thoroughly discuss the specific "Actions" listed in Table 3.

R: We thank the reviewer for this constructive suggestion. We have revised the manuscript to strengthen the focus on the role of recombinant vaccine platforms within health system preparedness frameworks, in line with the title of the review. The general discussion of preparedness frameworks has been condensed, while greater emphasis has been placed on how recombinant vaccines interact with and support these frameworks.

In addition, we have expanded the section on “Advantages and limitations for Public Health Preparedness” to address multiple recombinant and nucleic acid–based vaccine platforms, rather than focusing predominantly on mRNA vaccines. Platform-specific advantages and criticalities are now discussed to provide a more balanced and comprehensive analysis.

 

 

2- Most of the current discussion is based on COVID-19 pandemic, while recombinant technology did not start in 2019. By ignoring pre-COVID history, the current review is more like a retrospective on a single event rather than a forward-looking review of the technology. It would be highly beneficial to include examples of recombinant platforms applied to other disease, such as Ebola, influenza, HPV, etc. Including such examples would validate the authors' claims about recombinant platforms beyond the emergency use of 2020-2022.

R: We appreciate this comment and agree that relying predominantly on the COVID-19 pandemic could limit the forward-looking perspective of the review. To address this concern, we have expanded the manuscript to include pre-COVID examples of recombinant vaccine platforms applied to other infectious diseases, such as Ebola outbreaks and seasonal influenza, as well as well-established platforms including hepatitis B and human papillomavirus vaccines. These examples highlight that recombinant platforms were already mature and strategically relevant before 2019, and that the COVID-19 pandemic primarily accelerated their large-scale deployment rather than initiating their development.

At the same time, we believe that the COVID-19 pandemic represents a pivotal event in recent public health history; for this reason, it continues to receive substantial attention in the manuscript.

 

3- The manuscript only lists "Actions" theoretically in Table 3, but lacks of concrete action examples in real-world, such as how did the specific mechanisms (e.g., rolling reviews, emergency use authorization criteria for mRNA vs. protein subunits) utilized by agencies like the FDA or EMA. Such discussion will help transforming the manuscript from a general policy overview to a specific, mechanism-driven analysis of the technology's role in public health.

R: We thank the reviewer for highlighting the need for concrete, real-world examples. In expanding the section on actions, we have also included real-world examples to illustrate how these mechanisms have been applied in practice.

Reviewer 2 Report

Comments and Suggestions for Authors

Please find below comments and recommendations for the manuscript Vaccines-4057512.

Line 36: …..‘reflects’ should be corrected as ‘reflect’

Line 45: ….. ‘respond to this kind of health emergencies’

Please edit as ….. ‘respond to these kinds of health emergencies’

 

Lines 50-53: Not all platforms (covered here under recombinant types) offer a rapid mode of vaccine development and production. A new protein subunit-based vaccine still demands a significant amount of development and characterization time.  

 

Line 67: Recombinant vaccine platforms are not limited to ‘viral’ vaccines. The statement needs editing.

 

Line 78 and Table 1:

DNA vaccines: A DNA vaccine named ZyCoV-D (COVID-19) DNA vaccine developed by Zydus-Cadila was approved in India for clinical use and is administered through a needle-free delivery system. The following two references can be cited:

 

Momin T, et al, Safety and Immunogenicity of a DNA SARS-CoV-2 vaccine (ZyCoV-D): Results of an open-label, non-randomized phase I part of phase I/II clinical study by intradermal route in healthy subjects in India. EClinicalMedicine. 2021 Aug;38:101020. doi: 10.1016/j.eclinm.2021.101020. Epub 2021 Jul 17. PMID: 34308319.

 

Khobragade A et al, ZyCoV-D phase 3 Study Investigator Group. Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India. Lancet. 2022 Apr 2;399(10332):1313-1321. doi: 10.1016/S0140-6736(22)00151-9. PMID: 35367003.

 

Line 89-91: Specific references are required for each of the examples given (dengue, Zika, yellow fever, and tickborne encephalitis viruses).

 

Line 96: What does ‘modular design’ imply in the context of ‘swift adaptation to emerging variants’ here?

 

The statements appear to contradict at places: Such as Line 103 – ‘….allow for rapid design and production…..’ While it then mentions in Lines 112-120 ‘manufacturing complexity, related costs, can limit scalability, etc’.

 

Line 196: This line needs editing for correctness.

 

Liknes 198-199: These lines require some editing for correctness – remove ‘On the other hand’.

 

Line 208: What vaccines were reviewed by the EMA rolling review process and what products then were granted Conditional Marketing Authorization (CMA)? Please provide examples/details.  

 

Line 243: Reference is missing for the statement in this line.

 

Line 275: Please describe ‘reliance models’.

 

Overall, the manuscript largely focusses on  ‘importance and considerations for health system preparedness frameworks’ itself, rather than how recombinant vaccines play a role in the preparedness frameworks. Thus, this differs from what the title of the manuscript indicates.

 

Further, the manuscript primarily discusses the mRNA platform (Covid vaccine) as a representative example of recombinant vaccines.  Rather, the manuscript is expected to address both the advantages and limitations of each of the possible ‘recombinant’ or nucleic acid based vaccine platforms as separate cases.

 

Similarly, the section ‘Advantages and limitations for Public Health Preparedness’ also mentions only the mRNA platform.

 

The mRNA and DNA vaccines can be classified as ‘acid based vaccine’

 

Table 1: Item 1 for ‘Recombinant vaccines’, under ‘public health relevance’ mentions as “can be rapidly updated for new antigens”. This statement does not sound to fit as a feature here.

 

Table 3:

While all the “domains” mentioned in the table are valid points, these are already considered/ employed during the vaccine development process. Nevertheless, there is room for improvement in some of the sections, such as “Provide targeted training for healthcare workers for specific vaccine types, emphasizing handling, administration etc,…”.

List of all abbreviations can be provided at end, including for terms such as ECDC and EIB, full-forms of which are not provided in the text.

Author Response

Reviewer 2

Please find below comments and recommendations for the manuscript Vaccines-4057512.

Line 36: …..‘reflects’ should be corrected as ‘reflect’

R: We thank the reviewer for the comment. Upon careful review, we confirm that the subject of the sentence is “the frequency”; therefore, the use of the third person singular verb (“reflects”) is grammatically correct, and no change was required.

 

Line 45: ….. ‘respond to this kind of health emergencies’ Please edit as ….. ‘respond to these kinds of health emergencies’

Lines 50-53: Not all platforms (covered here under recombinant types) offer a rapid mode of vaccine development and production. A new protein subunit-based vaccine still demands a significant amount of development and characterization time. 

Line 67: Recombinant vaccine platforms are not limited to ‘viral’ vaccines. The statement needs editing.

R: Thank you for the comment. The sentences and wording have been revised accordingly.

 

Line 78 and Table 1:

DNA vaccines: A DNA vaccine named ZyCoV-D (COVID-19) DNA vaccine developed by Zydus-Cadila was approved in India for clinical use and is administered through a needle-free delivery system. The following two references can be cited:

 

Momin T, et al, Safety and Immunogenicity of a DNA SARS-CoV-2 vaccine (ZyCoV-D): Results of an open-label, non-randomized phase I part of phase I/II clinical study by intradermal route in healthy subjects in India. EClinicalMedicine. 2021 Aug;38:101020. doi: 10.1016/j.eclinm.2021.101020. Epub 2021 Jul 17. PMID: 34308319.

Khobragade A et al, ZyCoV-D phase 3 Study Investigator Group. Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India. Lancet. 2022 Apr 2;399(10332):1313-1321. doi: 10.1016/S0140-6736(22)00151-9. PMID: 35367003.

R: Thank you for the comment. We added it in the table and in the manuscript.

 

 Line 89-91: Specific references are required for each of the examples given (dengue, Zika, yellow fever, and tickborne encephalitis viruses).

R: Thank you for the comment. The examples provided (dengue, Zika, yellow fever, and tick-borne encephalitis viruses) are all addressed in reference 17, which focuses on the use of mRNA vaccine platforms against this group of pathogens. We have ensured that this reference is clearly associated with the relevant examples in the text.

Line 96: What does ‘modular design’ imply in the context of ‘swift adaptation to emerging variants’ here?

R: Thank you for the comment. In this context, “modular design” refers to the ability to rapidly replace the mRNA sequence encoding the antigen of interest while maintaining the same delivery platform and manufacturing process. This allows swift updates of vaccine candidates in response to emerging variants, as demonstrated during the development of SARS-CoV-2 variant–specific boosters.

 

The statements appear to contradict at places: Such as Line 103 – ‘….allow for rapid design and production…..’ While it then mentions in Lines 112-120 ‘manufacturing complexity, related costs, can limit scalability, etc’.

R: Thank you for the comment. The statements are not intended to be contradictory. The manuscript aims to distinguish between the intrinsic characteristics of recombinant vaccine platforms and the practical challenges associated with their implementation at scale. Recombinant technologies, particularly mRNA-based platforms, allow for rapid antigen design and adaptation once the necessary infrastructure is in place. However, establishing and maintaining the manufacturing pipeline, supply chain, and regulatory framework required for large-scale production remains complex and resource-intensive, as clearly demonstrated during the COVID-19 pandemic.

In response to the reviewer’s comments, we have clarified this distinction in the text and expanded the discussion to include platform-specific limitations beyond mRNA vaccines, highlighting that different criticalities emerge depending on the recombinant technology considered.

 

 

Line 196: This line needs editing for correctness. Liknes 198-199: These lines require some editing for correctness – remove ‘On the other hand’.

R: Thank you for the comment. The sentence has been revised accordingly.

 

Line 208: What vaccines were reviewed by the EMA rolling review process and what products then were granted Conditional Marketing Authorization (CMA)? Please provide examples/details. 

R: Thank you for the comment. We have revised the manuscript to explicitly list the five vaccines reviewed through the EMA rolling review process and subsequently granted CMA.

 

Line 243: Reference is missing for the statement in this line.

R: Thank you for the comment. The reference has been added.

 

Line 275: Please describe ‘reliance models’.

R: Thank you for the comment. We have added a description of regulatory reliance models, outlining how regulatory authorities may use evaluations conducted by other trusted agencies to facilitate and accelerate decision-making during emergencies.

 

Further, the manuscript primarily discusses the mRNA platform (Covid vaccine) as a representative example of recombinant vaccines.  Rather, the manuscript is expected to address both the advantages and limitations of each of the possible ‘recombinant’ or nucleic acid based vaccine platforms as separate cases.

R: We appreciate this comment and agree that a predominant focus on mRNA vaccines could limit the balance of the review. In response, we have expanded the manuscript to address the advantages and limitations of the different recombinant and nucleic acid–based vaccine platforms as separate cases, including mRNA, recombinant protein subunit, virus-like particle, viral vector, and DNA vaccines.

We have also incorporated examples beyond the COVID-19 pandemic, including pre-COVID applications such as Ebola outbreaks, seasonal influenza, and well-established platforms such as hepatitis B and human papillomavirus vaccines. These additions highlight that recombinant platforms were already mature and strategically relevant before 2019, while the COVID-19 pandemic primarily accelerated their large-scale deployment rather than initiating their development. Given its pivotal role in recent public health history, COVID-19 remains an important reference point throughout the manuscript.

Overall, the manuscript largely focusses on  ‘importance and considerations for health system preparedness frameworks’ itself, rather than how recombinant vaccines play a role in the preparedness frameworks. Thus, this differs from what the title of the manuscript indicates.

Similarly, the section ‘Advantages and limitations for Public Health Preparedness’ also mentions only the mRNA platform.

R: We thank the reviewer for these related comments. In response, we have revised the manuscript to strengthen the focus on the role of recombinant vaccine platforms within health system preparedness frameworks, in line with the title of the review. The general discussion of preparedness frameworks has been condensed, while greater emphasis has been placed on how recombinant vaccines interact with and support these frameworks.

In addition, we have expanded the section on “Advantages and limitations for Public Health Preparedness” to address multiple recombinant and nucleic acid–based vaccine platforms, rather than focusing predominantly on mRNA vaccines. Platform-specific advantages and criticalities are now discussed to provide a more balanced and comprehensive analysis.

The mRNA and DNA vaccines can be classified as ‘acid based vaccine’

R: We thank the reviewer for the comment. While mRNA and DNA vaccines are both based on the delivery of nucleic acids, in the manuscript they are treated as distinct vaccine platforms due to their different delivery systems, immunogenic profiles, manufacturing processes, and levels of regulatory maturity. For this reason, they are discussed separately throughout the review.

 

Table 1: Item 1 for ‘Recombinant vaccines’, under ‘public health relevance’ mentions as “can be rapidly updated for new antigens”. This statement does not sound to fit as a feature here.

R: Thank you for the comment. The sentence has been revised accordingly.

 

Table 3:While all the “domains” mentioned in the table are valid points, these are already considered/ employed during the vaccine development process. Nevertheless, there is room for improvement in some of the sections, such as “Provide targeted training for healthcare workers for specific vaccine types, emphasizing handling, administration etc,…”.

R: Thank you for the comment. The sentence has been revised accordingly.

 

List of all abbreviations can be provided at end, including for terms such as ECDC and EIB, full-forms of which are not provided in the text.

R: Thank you for the comment. Full forms of all abbreviations have been provided.

Reviewer 3 Report

Comments and Suggestions for Authors

This review by Russo et al examines the role of recombinant vaccine technologies in preparedness frameworks, while highlighting the practical challenges that remain in their deployment and integration. I have following comments for authors to consider for making the review more relevant and improve balance.

1.The way the review is currently written, there is an underlying assumption that the next pandemic may be also caused by viruses. As a result, there is only one sentence on potential pandemic infections caused by bacteria. If the authors want to keep the review broad and merely use the recent Covid-19 pandemic as a template, the authors will need to add sections focusing on bacterial infections as well. Alternatively, they specify the intent clearly and focus on infections caused by viruses and change the title accordingly.

2. I feel the emphasis on recombinant vaccine platforms need to be placed in context and associated difficulties as they are not easy to develop. Prior knowledge of targets is almost a must for rapid production. The targets need to be protective, conserved for counteracting antigenic variability and properly folded to encompass conformational and post translational modification containing epitopes. This is not a plug and play system and require a typical investment of close to 1 billion dollars for a generating a typical vaccine which includes the discovery, early and late development phases with substantial regulatory burden. The success of mRNA-based vaccines was due to parallel advancements in 1. structural and reverse vaccinology 2. SARS-CoV-2 being extremely vulnerable to neutralizing abs and 3. close to 10-billion-dollar investment in funding via government and non-governmental sources. Disease X may not be as susceptible to neutralizing Abs and plan of action for such an event may need to be added. This is where the killed or live attenuated vaccines find their space for some level of protection to prolong survival even if they are not as efficacious.

3. Although the topic focuses on recombinant vaccine platforms, a sentence or two on repurposed pathogen-directed drugs may be even more essential given the increased public skepticism on vaccine-based approaches in the developed world like USA. This may make the review balanced.

4. The authors list several coalition organizations established to improve pandemic response. However, these efforts still largely rely on the WHO for protocol development and coordination. Given current uncertainties surrounding the WHO’s capacity and role, the authors should consider discussing alternative or complementary frameworks for setting standards and coordination.

5. In addition, effective preparedness requires that individual countries maintain reliable pipelines for essential supplies. During the COVID 19 pandemic, access to critical items such as personal protective equipment and oxygen concentrators was delayed, in part due to overreliance on external manufacturing sources. Addressing supply chain diversification and domestic or regional production capacity would be something that can be discussed.

Author Response

Reviewer 3

This review by Russo et al examines the role of recombinant vaccine technologies in preparedness frameworks, while highlighting the practical challenges that remain in their deployment and integration. I have following comments for authors to consider for making the review more relevant and improve balance.

 

1.The way the review is currently written, there is an underlying assumption that the next pandemic may be also caused by viruses. As a result, there is only one sentence on potential pandemic infections caused by bacteria. If the authors want to keep the review broad and merely use the recent Covid-19 pandemic as a template, the authors will need to add sections focusing on bacterial infections as well. Alternatively, they specify the intent clearly and focus on infections caused by viruses and change the title accordingly.

R: We thank the reviewer for this important clarification. The intent of this review is to specifically focus on emerging viral diseases, for which recombinant vaccine platforms currently represent the most mature and strategically relevant preparedness tools.

To address this point, we have revised the manuscript to clearly state, from the introduction onward, that the scope of the review is intentionally limited to viral pathogens. Specifically, the introduction now reads:

 

2. I feel the emphasis on recombinant vaccine platforms need to be placed in context and associated difficulties as they are not easy to develop. Prior knowledge of targets is almost a must for rapid production. The targets need to be protective, conserved for counteracting antigenic variability and properly folded to encompass conformational and post translational modification containing epitopes. This is not a plug and play system and require a typical investment of close to 1 billion dollars for a generating a typical vaccine which includes the discovery, early and late development phases with substantial regulatory burden. The success of mRNA-based vaccines was due to parallel advancements in 1. structural and reverse vaccinology 2. SARS-CoV-2 being extremely vulnerable to neutralizing abs and 3. close to 10-billion-dollar investment in funding via government and non-governmental sources. Disease X may not be as susceptible to neutralizing Abs and plan of action for such an event may need to be added. This is where the killed or live attenuated vaccines find their space for some level of protection to prolong survival even if they are not as efficacious.

R: We thank the reviewer for this detailed and insightful comment. We have addressed these points by expanding the Advantages and limitations for Public Health Preparedness section to better contextualize the development of recombinant vaccine platforms and their associated challenges.

 

3. Although the topic focuses on recombinant vaccine platforms, a sentence or two on repurposed pathogen-directed drugs may be even more essential given the increased public skepticism on vaccine-based approaches in the developed world like USA. This may make the review balanced.

R: We thank the reviewer for this valuable suggestion. We agree that a balanced preparedness framework should acknowledge the complementary role of non-vaccine countermeasures, particularly in contexts where vaccine uptake may be limited by public skepticism. While the primary focus of this review remains on recombinant vaccine platforms, we have added a brief discussion in the preparedness section highlighting the role of repurposed pathogen-directed therapeutics as an adjunct to vaccination strategies. This addition underscores that effective preparedness relies on a layered approach, integrating vaccines with antiviral and other medical countermeasures, especially during the early phases of outbreaks or in settings with suboptimal vaccine acceptance.

4. The authors list several coalition organizations established to improve pandemic response. However, these efforts still largely rely on the WHO for protocol development and coordination. Given current uncertainties surrounding the WHO’s capacity and role, the authors should consider discussing alternative or complementary frameworks for setting standards and coordination.

R: We thank the reviewer for this important clarification. We agree that the WHO continues to play a central normative and coordinating role in global preparedness, and that current uncertainties related to its capacity and geopolitical context warrant critical reflection.

However, we would like to clarify that several initiatives listed in Table 2 operate outside direct WHO governance and represent complementary, multi-actor frameworks rather than WHO-led programs. In the manuscript, we highlight that global preparedness is progressively evolving toward a more distributed governance model, in which coordination, financing, manufacturing, and implementation are increasingly supported by complementary frameworks operating alongside, rather than independently from, WHO.

5. In addition, effective preparedness requires that individual countries maintain reliable pipelines for essential supplies. During the COVID 19 pandemic, access to critical items such as personal protective equipment and oxygen concentrators was delayed, in part due to overreliance on external manufacturing sources. Addressing supply chain diversification and domestic or regional production capacity would be something that can be discussed.

R: We thank the reviewer for highlighting this critical aspect of preparedness. We agree that pandemic response capacity depends not only on vaccines and therapeutics but also on reliable access to essential medical supplies. To address this point, we have added a paragraph discussing the vulnerabilities observed during the COVID-19 pandemic

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for addressing most of the comments raised during the first round of review process.

The abbreviation list could not be found however at the end of the manuscript, which can be added.