Structural Advances in Respiratory Syncytial Virus: Implications for Vaccine and Antiviral Development

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript reviews recent structural advances in respiratory syncytial virus (RSV) research and discusses their implications for vaccine and antiviral development. The topic is timely and important, and the manuscript contains several strengths. In particular, the overview of prefusion F structure, neutralizing epitopes, and the structural basis of currently licensed RSV vaccines is informative and potentially useful for readers in virology, structural biology, and translational vaccine research. The article is also well motivated by the substantial global disease burden of RSV and the rapid progress enabled by cryo-EM and cryo-ET.

However, in its current form, the manuscript still requires major revision before it can be considered for publication. My main concerns relate to the balance of the review, the level of mechanistic rigor in several sections, the insufficient integration of structural insights with antiviral development beyond F-focused prophylaxis, and the large number of language, figure-caption, and presentation issues throughout the text.

Major comments

1，The scope of the review is currently not fully aligned with the title.The title promises a broad discussion of “structural advances” in RSV and their implications for both vaccine and antiviral development. In practice, the manuscript is heavily centered on the F protein and on vaccine/passive immunization strategies, whereas the sections on other RSV proteins and non-F therapeutic targets remain comparatively brief and largely descriptive.

2，The entry and fusion model should be presented more cautiously and critically. The manuscript currently describes the sequence involving G-mediated attachment, followed by prefusion F engagement with IGF1R and then nucleolin, in a way that reads as a settled, linear mechanism. This topic is more complex, and the review should better distinguish between attachment factors, candidate receptors/coreceptors, and models supported in particular experimental systems. I strongly recommend revising this section to make clear which aspects are well established and which remain proposed or context-dependent.

3，The section on antiviral development needs greater structural and mechanistic depth.
One of the strengths claimed in the manuscript is that structures of the polymerase complex, matrix lattice, and other RSV components have broadened therapeutic targets beyond F. However, the later therapeutic section remains dominated by monoclonal antibodies and ribavirin, with limited mechanistic discussion of how structural biology has actually informed the development of direct-acting antivirals against L, N, or other viral proteins. This creates a disconnect between the early framing of the review and its later execution. A stronger antiviral section should explicitly connect structural findings to inhibitor-binding sites, mechanisms of action, resistance considerations, and clinical development status.

4，The manuscript would benefit from a clearer temporal framework for clinical and regulatory updates. Because the review discusses approvals and clinical progress across multiple years and products, the authors should state the literature cutoff date and consistently define whether regulatory status refers to the United States only or to broader international settings. This is especially important in a rapidly moving field, where “approved,” “in clinical trials,” and “discontinued” can quickly become outdated.

 

Minor comments

1, Substantial English editing is needed throughout the manuscript. There are numerous grammatical, typographical, and stylistic issues that reduce readability. Examples include:  “envelop” instead of “envelope” .

2, duplicated words such as “Three transmembrane glycoproteins proteins”

3, The manuscript should adopt one consistent style for terms such as prefusion/pre-fusion, postfusion/post-fusion, cryo-EM/cryoEM, immunocompromised/immuno-compromised, and RSV lower respiratory tract disease abbreviations.

4, Figure legends, especially for Figure 1 and Figure 2, require careful revision. Several legend sentences are grammatically incomplete or poorly punctuated. Abbreviations should be fully and consistently defined. In Figure 1, the definitions for M2-1 and M2-2 are incomplete in the caption, and spacing after punctuation is inconsistent.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The review titled “Structural Advances in Respiratory Syncytial Virus: Implications for Vaccine and Antiviral Development” offers a concise yet excellent introduction to the characteristics of RSV, while the other sections thoroughly explain every viral feature related to the infection.

I personally enjoyed reading this review, and including the PDB ID with the corresponding 3D structures, along with the EMDB ID, enhances understanding compared to traditional 2D representations. The information is well organized and aligns with the references.

 

The only observations are related to the quality of the following figures and tables:

Figure 1.- The words inside the boxes are blurry

Table 1.- The glossary of RSV proteins table, between the second and the third file, is misplaced, maybe some edition errors.

Figure 2.- Change the color of the viral membrane; they have very similar tonality, and it’s hard to differentiate between the host membrane.

Table 2.- Very good table with vital information. I suggest modifying the table structure, reducing the EMDB ID column width, and improving the resolution, since it looks like a screenshot.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This is a timely and potentially useful review. The manuscript covers RSV genome/virion architecture, fusion, vaccines, antibodies, antivirals, and future directions, and the core message that structural biology has directly shaped modern RSV prophylaxis appears to be relevant for Microorganisms. I only have a few remarks and suggest minor revision.

 

Major concerns:

1. Line 201 claims that RSV “carries out gradient transcription” but the cited reference is titled “Non-gradient and genotype-dependent patterns of RSV gene expression.” Please check whether the statement is correct since apparently at least some RSV isolate do not follow gradient transcription patterns.
2. There are many grammatical and stylistic issues that impair readability, including awkward captions, duplicated words/punctuation, and terminology inconsistencies.

Minor concerns:

3. Table 1 needs to be formatted better (e.g., some vertical lines are off).
4. Tables 2 & 3 also need to be reformatted; it appears that they have been pasted as images with low resolution.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I have no other comments.