Review Reports - The Yellow Fever Vaccine Journey: Milestones and Future Directions

Round 1

Reviewer 1 Report (Previous Reviewer 1)

Comments and Suggestions for Authors

The review "The yellow fever vaccine journey: milestones and future directions" chronicles the development, use and future directions of vaccines to prevent YF. The manuscript is poorly written and is not coherent in its structure. Many statements are repeated, almost identically, in various areas of the manuscript. I am not sure if this is a factor of having 14 authors, which is atypical for a review, but there needs to be substantial work to organize the efforts of so many individuals and it does not appear to have been done successfully. While the changes from the original version have improved the manuscript, it is not publishable in its current form. Therefore, it is my opinion that the manuscript should be rejected.

Major issues:

1- Repetition is rampant throughout the manuscript, with some statements being contradictory. For example, it is stated that one shot is needed to protect for life in lines 59-60, which is repeated in line 179-181. In lines 346-347 it states that vaccine provides 10 years of protection with a single injection. The other significant repeated information involves description of mosquitos. In lines 64-66 it suggests that the primary vectors are Aedes africans as well as Haemogogus and Sabethes species, which is true for circulation in a sylvatic cycle, but not for human infection (although it is not clarified if this spread refers to human or animal). The next line calls YFV a parasite, which is a bit misleading. A couple paragraphs later, there is reference to the sylvatic mosquito species in lines 90-92. Another repeated reference to the sylvatic mosquitos is made again in lines 107-108. Another reference top mosquito transmission is made in line 251-252. The manuscript needs to be better organized to discuss certain topics in a single section, rather than repeating the same information throughout the manuscript.

2- References are not appropriately placed after cited work. For example, lines 311-313 refer to previous studies, but no reference is included here. There are references included at the end of the paragraphs, but it is unclear what information these references contain. It is critical to refer to previously published data after summarizing the findings of such publications. Tables are also not placed in appropriate sections of the manuscript. For example, Table 2 is included after a statement of the vaccine development resulting in the Nobel prize (lines 156-158), but the table lists mutations observed after attenuation, which is referred to later in this section (lines 186-189).

3- The inclusion of unnecessary methods is included in the review manuscript. For example, Lines 215-220 include detail on Q anion exchange membrane extraction, when a simple reference to the method and a link to the original research would suffice. Conversely, further details of methods like BEVS would be helpful to understand how these systems are improving vaccine production, while the information provided is not detailed enough to draw out the conclusion that such a method would be helpful.

4- The manuscript has several examples of sentences and sections that are disjointed and not coherent. For example, line 194 refers to the devastating impact of YFV on the US, but then talks about CD8+ cells. This opening sentence has nothing to do with the paragraph it proceeds, at least as it now reads. This is also an issue with disjointed sections like the paragraph beginning on line 61. At the end of the paragraph it refers to the Aedes aegypti. A new paragraph begins and talks about this mosquito vector. It would be more cohesive if the last sentence is the start of a new paragraph discussing A. aegypti. There is also a reference to uncertainty in diagnosis of YFV in 1648 on line 62, but a few sentences later in line 68 it suggests that the first documented case occurred in 1648. Is it sure, or is it uncertain? In the abstract (lines 51-52) there is a reference to reemergence in previously non-endemic areas, but something can't reemerge when it hasn't yet emerged.

There are also numerous minor issues, but unless the major issues are resolved, these are inconsequential.

Comments on the Quality of English Language

The quality of English improved with the revision, but there are still several word usage issues that could be improved.

Author Response

We strongly disagree with this comment, both in content and in form, given the enormous effort put into this review and the importance of the topic. Nevertheless, we continued to improve our manuscript. The current version has additionally significantly improved.

Major issues:

Well, that is not a repetition. It was part of the emphasis on it.

In lines 346-347 it states that vaccine provides 10 years of protection with a single injection.

This has been deleted.

The other significant repeated information involves description of mosquitos. In lines 64-66 it suggests that the primary vectors are Aedes africans as well as Haemogogus and Sabethes species, which is true for circulation in a sylvatic cycle, but not for human infection (although it is not clarified if this spread refers to human or animal).

Corrected.

The next line calls YFV a parasite, which is a bit misleading.

Replaced by pathogen.

A couple paragraphs later, there is reference to the sylvatic mosquito species in lines 90-92.

Deleted.

Another repeated reference to the sylvatic mosquitos is made again in lines 107-108.

Deleted.

Another reference top mosquito transmission is made in line 251-252. The manuscript needs to be better organized to discuss certain topics in a single section, rather than repeating the same information throughout the manuscript.

Corrected.

Tables are also not placed in appropriate sections of the manuscript. For example, Table 2 is included after a statement of the vaccine development resulting in the Nobel prize (lines 156-158), but the table lists mutations observed after attenuation, which is referred to later in this section (lines 186-189).

Misplacement and call to Table 2 has been revised.

Revised. Deleted.

Conversely, further details of methods like BEVS would be helpful to understand how these systems are improving vaccine production, while the information provided is not detailed enough to draw out the conclusion that such a method would be helpful.

Now included, with a proper reference.

Revised. Deleted.

At the end of the paragraph it refers to the Aedes aegypti. A new paragraph begins and talks about this mosquito vector. It would be more cohesive if the last sentence is the start of a new paragraph discussing A. aegypti.

Revised.

There is also a reference to uncertainty in diagnosis of YFV in 1648 on line 62, but a few sentences later in line 68 it suggests that the first documented case occurred in 1648. Is it sure, or is it uncertain?

Revised.

In the abstract (lines 51-52) there is a reference to reemergence in previously non-endemic areas, but something can't reemerge when it hasn't yet emerged.

Revised. Corrected.

There are also numerous minor issues, but unless the major issues are resolved, these are inconsequential.

The manuscript has been completely revised.

Reviewer 2 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

The authors have updated the manuscript with current information and strong scientific analysis. With the above minor edits, the manuscript will be ready for publication in its present form.

The manuscript is current and thorough, incorporating historical milestones, epidemiological data, immunological insights, and policy frameworks, including the WHO EYE strategy. This scope renders it exceedingly beneficial to the discipline. The abstract is lucid, succinct, and systematically organized, adeptly harmonizing past accomplishments with contemporary obstacles and prospective trajectories. This versatility renders the evaluation both useful and fascinating for a diverse audience.

The incorporation of longitudinal vaccine coverage data (Table 1) and the examination of fractional dose techniques offer pragmatic, evidence based insights that enhance the manuscript's contribution to public health policy.

Minor Comments:

Maintain consistency in terminology by uniformly using “yellow fever virus (YFV)” and “yellow fever (YF)” throughout the manuscript for clarity.

Incorporating a conceptual picture or timeline that summarizes the three transmission cycles and the historical dissemination of yellow fever would improve clarity and imagery.

To improve intelligibility, several sections would benefit from grammatical refinement and enhanced coherence, particularly in the transition between epidemiological history and vaccine development. Please edit it accordingly.

Author Response

The authors have updated the manuscript with current information and strong scientific analysis. With the above minor edits, the manuscript will be ready for publication in its present form.

Thanks a lot for your comments.

Thanks again for your comments.

Minor Comments:

Maintain consistency in terminology by uniformly using “yellow fever virus (YFV)” and “yellow fever (YF)” throughout the manuscript for clarity.

Well, it is consistent, as YFY is only referring to the virus, and YF to the disease.

Incorporating a conceptual picture or timeline that summarizes the three transmission cycles and the historical dissemination of yellow fever would improve clarity and imagery.

Done. Now included. Figures, renumbered.

To improve intelligibility, several sections would benefit from grammatical refinement and enhanced coherence, particularly in the transition between epidemiological history and vaccine development. Please edit it accordingly.

Thanks. Editions and improvements across the text has been made.

Reviewer 3 Report (Previous Reviewer 3)

Comments and Suggestions for Authors

Although Figure 1 is cited in the text, the content shown in the figure is explained too sample. In addition, the logical relationship in the figure is not clear. Firstly, the cells in the middle are infected epithelial cells or merely dendritic cells. The released cytokines sitimulate immune cells also including T cells and Macrophages cell. The "cytokine T-cell" is not appropriate. The functions of activated Tcells are not only to activate B cells. Finally, it is not clear what kind of cells migrate to the lymph nodes. It is hoped that the cell types and their interrelationships in the figure can be presented more clearly.

Author Response

Figure was modified and significantly improved.

Reviewer 4 Report (Previous Reviewer 4)

Comments and Suggestions for Authors

This comprehensive review give full insights on TFV research. Hope some contents could be shorter and concise. There are some minor concens as follows.

Line 67-77, To tell the history of YF, it should be put behind Line 62, in front of In 2013.
Line 105-113, it refers to the mechanism of transmission, which should be put behind the Severity of YF.
Line 121, what’s eh stands for?
From Line 321-337, there could be another limitation of epitopes vaccine design, the T cell epitope may not only exist on antigenic proteins, but also the NS proteins. If there were references, please add.
Table 1, as refer to coverage rates, % should be added.

Author Response

This comprehensive review give full insights on TFV research. Hope some contents could be shorter and concise. There are some minor concens as follows.

Thanks for your comments.

Line 67-77, To tell the history of YF, it should be put behind Line 62, in front of In 2013.

Done. Reordered.

Line 105-113, it refers to the mechanism of transmission, which should be put behind the Severity of YF.

Done. Reordered.

Line 121, what’s eh stands for?

Whole sentence corrected.

From Line 321-337, there could be another limitation of epitopes vaccine design, the T cell epitope may not only exist on antigenic proteins, but also the NS proteins. If there were references, please add.

Done. Included, also with references about it.

Table 1, as refer to coverage rates, % should be added.

Done. Included.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript was very difficult to understand, had poor word usage and was very scattered and had contradictory citations. In the first paragraph of section 2. Milestones in Yellow Fever vaccine Development, the following issues were observed. Because of the numerous issues in this paragraph, I did not proceed as substantial effort is needed to make this work suitable for publication.

There is a reference to 400 million people being vaccinated, but later in the same paragraph it states that more than 500 million people have taken it.

It is unclear why there is a reference to vaccination rates in the US and nowhere else. It might be better to focus on vaccination rates in and out of the area of endemicity. There is also no reference for this claim.

A sentence states "Both live attenuated vaccines are currently in the second round of clinical trials." Which attenuated vaccines is this referring to? The current YFVax is clinically approved and is not undergoing clinical trials.

This claim that "...the other is engineered to produce antibodies specific to dengue dengue through genetic modification." The vaccine doesn't produce antibodies. This statement does not make sense. Also, are you discussing a YFV vaccine or a DENV vaccine here? It is just very confusing. "It will go into phase 3 studies..." again, it is difficult to tell if you are talking about a DENV vaccine here based on the YFV backbone.

"...is a tiny icosahedral..." I would state the size of the virus, not just say it is tiny.

The sentence "So far, the chemical basis of 17D attenuation remains unknown." is not entirely true and many regions have been identified that contribute to attenuated nature of the vaccine virus.

"To keep one's immune system strong..." This should be removed. The vaccine is not administered to strengthen the immune system, but rather bolster the immunity to YFV.

It is stated that "...yellow fever spread worldwide..." is not right. It spread to various areas in the North and South America from Africa. Also, why is the United States highlighted here?

"Mosquito larvae carried the virus..." It is typically spread by adult female mosquitos, not the larvae.

"...patients died from symptoms like fever, jaundice and hemorrhages." People who died may have exhibited these symptoms of disease, but that does not mean they died of jaundice.

Again, all of the mistakes above were in a single paragraph. I do not recommend publishing this article.

Comments on the Quality of English Language

The language can be a bit colloquial and should be modified to a more scientific writing style. The main concern is that the sentences of some sections are jumbled and don't logically follow each other in an understandable or helpful way. Substantial rewriting of this manuscript is recommended.

Reviewer 2 Report

Comments and Suggestions for Authors

The review covers major section of yellow fever but still need some modifications in the revised manuscript.

Introduction:

What ecological factors contribute to the geographic expansion of Aedes aegypti?

What are the differences between the sylvatic, intermediate, and urban transmission cycles of yellow fever? Elaborate it in the introduction section.

What strategies can be used to close the vaccination gap and achieve WHO’s 80% coverage target? Explain it ..

How might climate change and urbanization influence future yellow fever outbreaks in non-endemic areas? Justify it…

Vaccine Safety issue is missing in the manuscript.

Please mention 1) How does the safety profile of the yellow fever vaccine compare to other live-attenuated vaccines? 2) What improvements in vaccine formulation or delivery could reduce adverse reactions?

Section 2.

What are the key areas for future research and development in yellow fever vaccine technology? Input a brief information…

What is the role of CD8+ T cells in long-term protection induced by the 17D vaccine?

How does IFN-γ limit YF viral replication compared to wild-type strains?

Could next-generation vaccine platforms (e.g., mRNA or viral vector-based) offer safer or more efficient yellow fever immunization? Explain in detail…

Line 119: Both live attenuated… which one, clarify it

Line 134: premonitory replace with quarantine

Why does the 17D vaccine remain effective despite having an unknown attenuation mechanism? Explain it..

Line 196: sixteen percent should be 16%

Which computational tools are most accurate in predicting B-cell and T-cell epitopes for flaviviruses? Explain with justification and references

Can epitope-based vaccines offer cross-protection across YFV genotypes from different continents (Africa vs. South America)? If yes, then explain in detail.

What are the major limitations of in silico predicted antigens in clinical settings? Elaborate it …

How soon could epitope-based vaccines realistically replace live-attenuated ones in yellow fever control programs? Any data available, if yes then input the detail…

Why is a booster dose not recommended for the general population despite possible waning antibody levels?

Figure 1 … update more pictorial with 300 dpi image

Line 302: We examine the various reactions… We ; is not consistent in academic tone.. Rewrite

Line 312: Tscm : Abbreviate it… Tscm, first time use in the manuscript..

There are some question to be address in the revised manuscript

Innate Immunity: How do increased IL-10+ monocytes contribute to both anti-inflammatory and regulatory roles during vaccination? What is the significance of Fc receptor upregulation in the context of vaccine-induced innate memory?

Adaptive Immunity: What is the threshold of neutralizing antibodies (PRNT50) used to define protection? Why does the booster dose reduce immune response in individuals with high baseline antibodies? Is this immune interference or antigenic competition?

Were any HLA alleles found to influence CD8+ T-cell memory response magnitude?

Section 4

Line 325: bad reactions convert to adverse reactions

Are there any biomarkers or predictive indicators currently used to assess a patient's risk before administering the yellow fever vaccine? If yes, then please input detail

Why is the highest rate of anaphylaxis reported specifically in 18-year-olds? Please input this information in the revised manuscript

Line 339: upper respiratory symptoms should be modified as upper respiratory symptoms (such as; nasal congestion, sore throat)

Line 347: "22-year-old African American lady" very formal language.. Convert the sentence as "a 22-year-old African American woman"

Why might older individuals be more susceptible to viscerotropic or neurotropic disease? Is this linked to age-related immune decline or comorbidities?

Section 5

How is international air travel regulated to prevent the spread of yellow fever via infected travelers or mosquitoes in aircraft…

During the Senegal pandemic (2020–2021): How effective was the collaboration between national and international institutions in managing the outbreak? Were any novel tools (genomic surveillance, AI for outbreak prediction, mobile labs) used?

Section 6

mRNA vaccines have shown success in preclinical models—what are the barriers to transitioning these into human trials for yellow fever?

Regarding Brighton Collaboration V3SWG: What specific safety risks have been associated with recombinant viral vectors carrying heterologous viral genes?

What role does monkey surveillance play in early outbreak detection, and how reliable is it compared to human case tracking? Is this information justified? Please clarify !!

Particularly Brazil, In the Minas Gerais 2021 case: What measures were implemented post-detection to prevent human transmission? Was the detected virus genetically characterized?

Section 7

What are the limitations in vector control interventions in forested environments compared to urban zones?

Why is swine susceptibility to flaviviruses (like JEV, WNV) important for yellow fever modeling, given yellow fever's traditional non-human primate cycle? Justify this !!

Section 8

Why was a formal systematic review or meta-analysis not conducted, and could that omission affect evidence grading?

Section 9

How feasible is the universal vaccination goal, given current vaccine production capacities and global demand?

The WHO stockpile system: How quickly can it be mobilized during an emergency? Are regional reserves adequately maintained?

Reviewer 3 Report

Comments and Suggestions for Authors

The content of this review has been well designed , but a few parts need to be improved.

1. Abstract: The abstract shuld summarize the key findings.

2. Systems collaborate innate and adaptive immunologies in vaccine-induced protection should be discussed.

3. The changes and opportunities of mRNA，nanoparticle-based vaccines should be discussed.

4. The rows in table1 are inconsistent with those in table2.

5. The description of immune reponse in figure 1 is useful, but the figures should be listed in some order (eg:1,2) to enhance understanding greatly.

6. The inverted words in Figure 2 are not easy to read.

7. The capitalize first letter of some titles are not consistent with others.

Reviewer 4 Report

Comments and Suggestions for Authors

This comprehensive review give the reader a full understanding of the YF vaccine. However, there are some concerns as follows.

Line 127, between 104 and 106 pfu, 104 and 106 should be 10^4 and 10^6.
Line 258, should be considered if persistently high, if what persistently high?
Line 588-592, the senteces seemed have no connections with this section, and the section title should be reconsidered.
During the history of YF vaccine development, if the mutations in 17D, 17D-204 ,17DD/YF-17D-231/77 could be listed in a table by comparing to parental virus, that would be great.