Integrated mechanistic and serological analyses reveal determinants of antibody-dependent enhancement in respiratory coronaviruses
- 1Pharmacological Evaluation Research Center, China State Institute of Pharmaceutical Industry
- 2Shanghai InnoStar Bio-tech Co., Ltd. (InnoStar)
Abstract
Background: Antibody-dependent enhancement (ADE) is an important concern in viral infection, vaccine development, and antibody-based therapeutics. Although extensively studied in flaviviruses, the molecular mechanisms and epidemiological relevance of ADE in respiratory coronaviruses remain incompletely understood. This study aimed to investigate the epitope-specific mechanisms, cellular pathways, and population characteristics of ADE mediated by SARS-CoV-2 and MERS-CoV antibodies.
Methods: SARS-CoV-2 and MERS-CoV pseudovirus ADE models were established using Fcγ receptor-expressing cells. The effects of epitope-specific antibodies, Fc–FcR interaction blockade, and inhibitors targeting Fyn, neuropilin-1 (NRP1), endosomal acidification, cathepsins, and PIKfyve were evaluated. A CD32B-based ADE model was developed for retrospective analysis of 530 human serum samples collected from 2019 to 2026. Cytokine profiles were analyzed in 175 serum samples. Correlations between antibody levels, ADE and inflammatory markers were statistically evaluated.
Results: Antibodies targeting specific epitopes within coronavirus spike proteins induced ADE of both SARS-CoV-2 and MERS-CoV pseudoviruses in FcγR-expressing cells. ADE was abolished by blocking Fc–FcR interactions, confirming Fc receptor dependence. ADE induction showed a concentration- and viral load-dependent pattern, with higher viral loads requiring increased antibody concentrations for maximal enhancement. Pharmacological inhibition revealed substantial overlap between ADE and classical receptor-mediated viral entry pathways, involving Fyn signaling, NRP1, endosomal acidification, cathepsins, and PIKfyve. Analysis of clinical serum samples demonstrated a significant association between antibody levels and ADE, with ADE incidence peaking during 2023 and remaining elevated thereafter. Serum samples capable of inducing ADE exhibited altered levels of TNF-α and IL-12p70, indicating that there may be enhanced activation of Th1 and increased pro-inflammatory responses.
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BibTeX
@article{xu2026integrated,
title = {{Integrated mechanistic and serological analyses reveal determinants of antibody-dependent enhancement in respiratory coronaviruses}},
author = {Tingting Xu and Yu Jiang and Chenjie Li and Huaying Chen and Zhipeng Zhang and Heng Zhang and Yunliang Qiu and Lu Zhou},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1967945},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1967945/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrated mechanistic and serological analyses reveal determinants of antibody-dependent enhancement in respiratory coronaviruses
AU - Tingting Xu
AU - Yu Jiang
AU - Chenjie Li
AU - Huaying Chen
AU - Zhipeng Zhang
AU - Heng Zhang
AU - Yunliang Qiu
AU - Lu Zhou
PY - 2026
DA - 2026/10/23
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1967945
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1967945/full
AB - Background: Antibody-dependent enhancement (ADE) is an important concern in viral infection, vaccine development, and antibody-based therapeutics. Although extensively studied in flaviviruses, the molecular mechanisms and epidemiological relevance of ADE in respiratory coronaviruses remain incompletely understood. This study aimed to investigate the epitope-specific mechanisms, cellular pathways, and population characteristics of ADE mediated by SARS-CoV-2 and MERS-CoV antibodies. Methods: SARS-CoV-2 and MERS-CoV pseudovirus ADE models were established using Fcγ receptor-expressing cells. The effects of epitope-specific antibodies, Fc–FcR interaction blockade, and inhibitors targeting Fyn, neuropilin-1 (NRP1), endosomal acidification, cathepsins, and PIKfyve were evaluated. A CD32B-based ADE model was developed for retrospective analysis of 530 human serum samples collected from 2019 to 2026. Cytokine profiles were analyzed in 175 serum samples. Correlations between antibody levels, ADE and inflammatory markers were statistically evaluated. Results: Antibodies targeting specific epitopes within coronavirus spike proteins induced ADE of both SARS-CoV-2 and MERS-CoV pseudoviruses in FcγR-expressing cells. ADE was abolished by blocking Fc–FcR interactions, confirming Fc receptor dependence. ADE induction showed a concentration- and viral load-dependent pattern, with higher viral loads requiring increased antibody concentrations for maximal enhancement. Pharmacological inhibition revealed substantial overlap between ADE and classical receptor-mediated viral entry pathways, involving Fyn signaling, NRP1, endosomal acidification, cathepsins, and PIKfyve. Analysis of clinical serum samples demonstrated a significant association between antibody levels and ADE, with ADE incidence peaking during 2023 and remaining elevated thereafter. Serum samples capable of inducing ADE exhibited altered levels of TNF-α and IL-12p70, indicating that there may be enhanced activation of Th1 and increased pro-inflammatory responses.
SN - 1664-3224
ER -