PREreview of Functional Antibody-Dependent Enhancement as an Immune Assessment Platform: Development, Standardization, and Translational Interpretation in Flavivirus Research

Summary

This review article provides a timely and comprehensive synthesis of Antibody-Dependent Enhancement (ADE) in the context of flavivirus research. It successfully argues for a paradigm shift: moving from treating ADE as a binary "risk factor" to utilizing it as a standardized, multidimensional "immune assessment platform." The author effectively outlines the technical requirements for standardization (target cell selection, viral input, and quantitative metrics) and highlights the translational value of these platforms for vaccine development and population surveillance. The manuscript is well-structured, the figures are of high conceptual quality, and the emphasis on methodological governance is a significant contribution to the field.

Major Strengths

Emphasis on Standardization: The most valuable contribution of this review is the "Modular Architecture" (Figure 2) and the "Standardized Metric Framework" (Figure 3). The field has long suffered from inter-laboratory variability; by defining

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, and reporting standards, this paper provides a roadmap for reproducibility.

1. Conceptual Clarity: The author does an excellent job of reframing ADE not as an "intrinsic property" of an antibody, but as a "functional state" dependent on concentration and biological context.

2. Visual Aids: The figures are exceptional. Figure 4, in particular, provides a very clear longitudinal view of how antibody profiles shift from enhancement-prone to neutralization-dominant after secondary infection.

3. Forward-Looking Scope: The integration of "Systems Immunology" and "Predictive Modeling" (Section 3.3 and 4.4) ensures the review is relevant for next-generation vaccine design.

4. AI Disclosure: Author has disclosed AI usage and its purpose in the article and ensure article is not a full reflection of the generative AI contents. Also instrumental for publication transparency.

Areas for Improvement & Constructive Feedback

1. Technical Nuance: FcγR Polymorphisms

In Section 2.3, the author mentions that receptor polymorphisms (e.g., FcγRIIA) are key variables. Given that this review advocates for "Standardized Platforms," it would be beneficial to include a brief discussion or a recommendation on how platforms should handle common polymorphisms (like the H131R variant in FcγRIIa) in their standardized cell lines. Should labs use a specific variant as a "gold standard," or should they test a panel?

2. Practical Implementation in LMICs

Flaviviruses are primarily endemic in Low- and Middle-Income Countries (LMICs). While the paper discusses "inter-laboratory transfer," it would strengthen the review to include a brief paragraph on the feasibility and cost-effectiveness of these platforms. For example, comparing the resource requirements of live-virus plaque assays versus reporter virus systems or SRIPs in resource-limited settings.

3. Specificity in "Vaccine Failure" Cases

In Section 5, the author notes that ADE shouldn't be seen as an "intrinsic marker of vaccine failure." The review would be more impactful if it briefly cited the specific lessons learned from the Dengvaxia (CYD-TDV) experience or other recent trials where the lack of these standardized ADE metrics may have hindered early risk stratification.

4. Terminology: Intrinsic vs. Extrinsic ADE

The paper mentions "extrinsic" (entry-level) and "intrinsic" (post-entry signaling) ADE (Section 2.3). It would be helpful to clarify if the proposed "Standardized Platform" is intended to measure both, or if current high-throughput platforms (like reporter viruses) are primarily limited to measuring extrinsic ADE.

Minor Points and Typographical Corrections

• OCR/Typo Check: There is a recurring typo throughout the document (likely from the drafting process): the word "settings" is frequently misspelled as "seings" (e.g., Page 3, 5, 9, 13, 14, 15).

• Figure 1 Legend: Ensure the mention of "Moi et al., 2010–2012" in the legend is explicitly linked to the references provided in the bibliography to help readers trace the origin of the first transferable platforms.

• Abbreviations: The abbreviation list is comprehensive, but ensure "SRIP" (Single-Round Infectious Particle) is used consistently, as some sections refer to "pseudotypes" interchangeably.

Final Recommendation

This is a high-quality review that will likely become a standard reference for laboratories establishing ADE assays. Once the minor typographical errors (e.g., "seings") are corrected and the technical points regarding polymorphism/LMIC implementation are considered, this manuscript will be an excellent addition to the literature.

Competing interests

The author declares that they have no competing interests.

Use of Artificial Intelligence (AI)

The author declares that they did not use generative AI to come up with new ideas for their review.