Cross-Protection in PRRSV: Mechanisms, Limitations, and Implications for Vaccine Design
, Limeng Cai 2, Nina Muro 1,2, Rachel Madera 1,2, Lihua Wang 1,2 and Jishu Shi 1,2,*
Ramon Zegpi Lagos
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis review focuses on the key issues in the immune protection of PRRSV-the immune mechanism and virus determinants of homologous, heterologous and cross-species protection, and the topic selection has important scientific significance and clinical application value. The article has a clear structure and abundant references, especially in the discussion of T cell immunity, antibody response and virus structural characteristics.
However, although the content is detailed, there are still some shortcomings in logical coherence, depth of information integration, structural arrangement and accuracy of expression, and it is suggested that the following aspects be revised and improved:
- There are many overlapping contents in the article. For example, the discussion on "T cell immunity" and "antibody response" appears repeatedly in several chapters, lacking progressive relationship. It is suggested to integrate relevant contents, avoid repeated narration and enhance organization.
- Figure 1 and Table 1 provide abundant phylogenetic data, but the results are not fully interpreted and applied in the text. It is suggested that the selection basis of these strains and their correlation with the follow-up discussion should be clearly stated in the corresponding paragraphs.
- For example, when discussing "asymmetric cross-species protection between PRRSV-1 and PRRSV-2", some conclusions are based on limited experimental data, and it is suggested to express them in a more cautious tone and clearly point out the limitations of the data.
- Section 6.5 discusses the "potential disadvantages of pre-existing immunity", but the content is scattered, which fails to deeply analyze the mechanism, controversy and practical significance of ADE in PRRSV. It is suggested to sort out this topic in combination with more literature systems.
- Some paragraphs have long sentences and low information density, which affects the reading experience. It is suggested to simplify the expression and highlight the key points. For example, in the "T cell immunity" section, the concepts of "IFN-γ" and "CD4/CD8" are repeated many times, which lacks the integration of different research conclusions.
- Although the title of Section 7 is "Summary and Future Outlook", the content is still mainly retrospective, and the discussion on the future direction is not specific enough. It is suggested that several key technical paths or research directions be clearly put forward, such as "antigen design based on structural vaccinology" and "T cell epitope vaccine".
- The same document has been cited many times in the text, and the citation in some paragraphs is seriously piled up. It is suggested to combine the citations and choose the most representative literature to support the argument.
Author Response
We thank the reviewer for their thoughtful and constructive feedback. We have carefully considered all comments and revised the manuscript accordingly. Our point-by-point responses are provided below, and all changes have been clearly indicated in the revised manuscript.
This review focuses on the key issues in the immune protection of PRRSV-the immune mechanism and virus determinants of homologous, heterologous and cross-species protection, and the topic selection has important scientific significance and clinical application value. The article has a clear structure and abundant references, especially in the discussion of T cell immunity, antibody response and virus structural characteristics.
However, although the content is detailed, there are still some shortcomings in logical coherence, depth of information integration, structural arrangement and accuracy of expression, and it is suggested that the following aspects be revised and improved:
1. There are many overlapping contents in the article. For example, the discussion on "T cell immunity" and "antibody response" appears repeatedly in several chapters, lacking progressive relationship. It is suggested to integrate relevant contents, avoid repeated narration and enhance organization.
AU: We thank the reviewer for this helpful and constructive comment. The manuscript has been revised (LL 411-427; 445-446; 477-479) to improve overall organization and reduce conceptual overlap between sections. Mechanistic descriptions of T-cell and antibody responses have been consolidated, and repetitive explanations in later sections have been replaced with cross-references.
2. Figure 1 and Table 1 provide abundant phylogenetic data, but the results are not fully interpreted and applied in the text. It is suggested that the selection basis of these strains and their correlation with the follow-up discussion should be clearly stated in the corresponding paragraphs.
AU: We thank the reviewer for this insightful comment. We have revised (LL 85-95) the figure legend to more clearly describe the rationale for strain selection and to highlight the key phylogenetic observations, including the limited diversity of vaccine strains and their relationship to contemporary field isolates.
3. For example, when discussing "asymmetric cross-species protection between PRRSV-1 and PRRSV-2", some conclusions are based on limited experimental data, and it is suggested to express them in a more cautious tone and clearly point out the limitations of the data.
AU: We thank the reviewer for this important comment. We have revised (LL 128-163) this section to adopt a more cautious and balanced tone and to explicitly acknowledge the limitations of the available data. In particular, we now emphasize the heterogeneity and limited number of studies, clarify that conclusions regarding asymmetric cross-species protection are based on constrained experimental evidence, and highlight that the biological relevance of these findings under field conditions remains uncertain.
4. Section 6.5 discusses the "potential disadvantages of pre-existing immunity", but the content is scattered, which fails to deeply analyze the mechanism, controversy and practical significance of ADE in PRRSV. It is suggested to sort out this topic in combination with more literature systems.
AU: We appreciate this insightful comment. We have revised Section 6.5 (LL505-541) to improve its structure and provide a more systematic discussion of the potential disadvantages of pre-existing immunity, with a clearer focus on antibody-dependent enhancement (ADE) in PRRSV. Specifically, we reorganized the section to (i) outline the proposed mechanisms of ADE based on in vitro studies, including Fc receptor–mediated uptake and modulation of antiviral responses, (ii) critically evaluate the existing evidence and highlight the ongoing controversy regarding the in vivo relevance of ADE in PRRSV infection, and (iii) discuss the practical implications for vaccination strategies, particularly in the context of heterologous challenge. We also refined the text to distinguish between antibody-mediated and broader immune-mediated mechanisms to improve clarity and coherence.
5. Some paragraphs have long sentences and low information density, which affects the reading experience. It is suggested to simplify the expression and highlight the key points. For example, in the "T cell immunity" section, the concepts of "IFN-γ" and "CD4/CD8" are repeated many times, which lacks the integration of different research conclusions.
AU: We thank the reviewer for this helpful comment. The section (LL 308-355) has been revised to improve clarity, reduce redundancy, and better integrate findings across studies, with a more concise presentation of key concepts (e.g., IFN-γ responses and CD4⁺/CD8⁺ T-cell roles).
6. Although the title of Section 7 is "Summary and Future Outlook", the content is still mainly retrospective, and the discussion on the future direction is not specific enough. It is suggested that several key technical paths or research directions be clearly put forward, such as "antigen design based on structural vaccinology" and "T cell epitope vaccine".
AU: We thank the reviewer for this valuable suggestion. The “Summary and Future Perspectives” section has been expanded (LL 561-588) to include more specific and actionable future research directions, including structure-guided antigen design, T-cell epitope–based vaccine strategies, and rational engineering of vaccine strains.
7. The same document has been cited many times in the text, and the citation in some paragraphs is seriously piled up. It is suggested to combine the citations and choose the most representative literature to support the argument.
AU: We thank the reviewer for this helpful comment. Citations in the main text have been streamlined to reduce redundancy and improve readability, while comprehensive referencing has been retained in the tables to provide full coverage of the available studies.
Reviewer 2 Report
Comments and Suggestions for AuthorsLines:
47 to 52: please add references
It may be possible to reduce the size of all Tables.
336 to 340: please add references
410 to 411: please add references
Good review, thorough and well written.
Would it be possible to include more information about mucosal/local immunity?
Author Response
We thank the reviewer for their thoughtful and constructive feedback. We have carefully considered all comments and revised the manuscript accordingly. Our point-by-point responses are provided below, and all changes have been clearly indicated in the revised manuscript.
1. 47 to 52: please add references
AU: We thank the reviewer for this helpful comment. References have been added to support the statement on the geographic distribution of PRRSV species.
2. It may be possible to reduce the size of all Tables.
AU: We thank the reviewer for this suggestion. The tables have been reformatted to improve readability and overall presentation.
3. 336 to 340: please add references
AU: We thank the reviewer for this helpful comment. Representative references have been added to support the summary statement regarding variability of T-cell responses.
4. 410 to 411: please add references
AU: We thank the reviewer for this helpful comment. References have been added to support the role of antibodies targeting conserved conformational epitopes as correlates of protection.
5. Good review, thorough and well written.
AU: We thank the reviewer for the positive evaluation of our manuscript.
6. Would it be possible to include more information about mucosal/local immunity?
AU: We thank the reviewer for this helpful suggestion. A paragraph on mucosal humoral immunity, including the role of IgA, has been added to Section 5.2 to address local immune responses to PRRSV. As a result, the “Summary and Future Outlook” section has been revised to more explicitly outline key research directions, including the integration of systemic and mucosal immunity as a framework for defining correlates of protection and guiding next-generation vaccine strategies.
