The Impact of IgG Glycosylation in SARS-CoV-2 Infection vs. Vaccination: A Statistical Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article is devoted to an interesting and important topic: the properties of antibodies to coronavirus after infection and vaccination. However, there are several serious limitations.

It is particularly surprising that the number of bases in the studied groups is not indicated anywhere. Nowhere in the figure legends is the number of bases in the study groups indicated.

For Figure 1, statistical significance (P values) for the obtained correlation coefficients must be provided.

The patient groups and their main characteristics must be clearly stated in the materials and methods. Otherwise, the study design is completely unclear.

In "Conclusions", the authors indicate: "This complexity suggests that specific  glycan markers could serve as potential biomarkers for differentiating immune responses, which may have important implications for clinical diagnostics and therapeutic strategies".  It is necessary to indicate more specifically for which diagnostics and therapeutic strategies this can be used.

And also, in the conclusion the authors point out that "... exploring the functional implications of specific glycan modifications will enhance our understanding of their roles in antibody efficacy and immune modulation". It is necessary to explain in detail how exactly glycan modifications can influence antibody efficacy and immune modulation.

Author Response

Point-by-Point Responses to Reviewer Comments

1. Number of Bases in Study Groups:
   • Thank you for highlighting the need for clarity. We have added the number of bases in each study group to the figure legends to enhance transparency.

2. Statistical Significance in Figure 1:
   • We appreciate your suggestion regarding statistical rigor. P values for the correlation coefficients have now been included in Figure 1 to substantiate our findings.

3. Clarity on Patient Groups:
   • Your feedback on the materials and methods section is invaluable. We have taken the liberty of explicitly stating the characteristics of the patient groups to provide a clearer understanding of our study design.

4. Specificity in Conclusions:
   • Thank you for pointing out the need for specificity in our conclusions. We have elaborated on the specific diagnostics and therapeutic strategies related to glycan markers to clarify their clinical implications.

5. Detail on Glycan Modifications:
   • We recognize the importance of further detail regarding glycan modifications. An expanded explanation of how these modifications influence antibody efficacy and immune modulation has been included in the revised manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

This article focuses on the glycosylation patterns of serum IgG antibodies in SARS-CoV-2 infection and vaccination, and through statistical analysis, reveals their impact on the immune response and its clinical significance. This article emphasizes the crucial role of IgG glycosylation in the immune response to COVID-19, providing a new perspective for immune assessment and clinical intervention. However, the document needs to be fixed before the final decision.

1: To apply specific glycan markers to clinical diagnosis and treatment strategies, what specific further studies need to be conducted? For instance, what feasible research designs are available in terms of large-scale population validation and longitudinal studies?

2: Demographic characteristics and disease severity, as systemic physiological factors, influence the interaction network among polysaccharide types through the integration process of glycosylation, thereby altering the complex dynamics of the immune response. How do the demographic characteristics of the patients and the severity of their diseases affect the interrelationship between the types of glycans and the overall dynamics of the immune response?

3: “The ongoing COVID-19 pandemic has catalyzed extensive research into the immune responses elicited by both natural infection and vaccination, as understanding these responses is critical for developing effective diagnostic tools and therapeutic strategies”. The COVID-19 pandemic has ended. Please rephrase the language and correct the related expressions.

4: The functional significance of specific glycosylation modifications remains insufficiently explored, warranting further investigation into their roles in antibody efficacy and immune regulation.

Author Response

Point-by-Point Responses to Reviewer Comments

1. Further Studies for Glycan Markers in Clinical Application:
   • Thank you for your insightful question regarding the application of specific glycan markers in clinical diagnostics and treatment. We acknowledge the need for additional studies and suggest the following research designs:
     • Large-Scale Population Validation: Conducting multicenter cohort studies to validate glycan markers across diverse populations.
     • Longitudinal Studies: Implementing longitudinal research to track glycan modifications over time in response to vaccination and infection, which will help establish causal relationships and monitor immune dynamics.

2. Impact of Demographic Characteristics and Disease Severity:
   • We appreciate your emphasis on the influence of demographic factors and disease severity on glycosylation dynamics. The revised manuscript will explore how these characteristics may alter the interrelationship between glycan types and immune response dynamics. Specifically, we will detail how variations in age, sex, and comorbidities may influence glycan profiles and their functional implications in the immune modulation process.

3. Rephrasing of Pandemic Context:
   • Thank you for pointing out the need for updated language regarding the COVID-19 pandemic. We will rephrase the relevant sections to reflect the current understanding, stating: “The COVID-19 pandemic has prompted extensive research into the immune responses elicited by both natural infection and vaccination, underscoring the importance of these responses in the development of effective diagnostic tools and therapeutic strategies.”

4. Exploration of Glycosylation Modifications:
   • We acknowledge your observation regarding the functional significance of glycosylation modifications. The manuscript will be revised to emphasize the necessity for further investigations into how specific glycan modifications affect antibody efficacy and immune regulation. We will propose potential experimental designs and methodologies to explore these functional roles in future studies.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the authors for taking my comments into account. However, the expanded discussion of the influence of glycosylation on antibody properties is too brief, lacking any references. The authors should add references to the relevant literature in this section of the discussion.

Author Response

We thank the reviewer for this insightful comment. We agree that the discussion of glycosylation’s impact on antibody properties required more depth and scholarly support. We have now significantly expanded this section to include a detailed mechanistic overview of how sialylation, fucosylation, and galactosylation influence Fc-mediated effector functions (ADCC, CDC, and anti-inflammatory signaling), supported by 8 additional references to foundational and recent literature.