SARS-CoV-2 antibody–dependent enhancement of infection depends on antibody binding to both ACE2 and Fc receptors
Natalia A. Kuzmina, Sivakumar Periasamy, Kritika Kedarinath, Keziah Hernandez, Caroline Atyeo, S. Moses Dennison, Kan Li, Daniel Bedinger, Sharon L. Schendel, Georgia D. Tomaras, Hanif Ali, Galit Alter, Erica Ollmann Saphire, Alexander Bukreyev
Natalia A. Kuzmina, Sivakumar Periasamy, Kritika Kedarinath, Keziah Hernandez, Caroline Atyeo, S. Moses Dennison, Kan Li, Daniel Bedinger, Sharon L. Schendel, Georgia D. Tomaras, Hanif Ali, Galit Alter, Erica Ollmann Saphire, Alexander Bukreyev
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Research Article Immunology Virology

SARS-CoV-2 antibody–dependent enhancement of infection depends on antibody binding to both ACE2 and Fc receptors

Abstract

Antibody-dependent enhancement (ADE) of infection is a well-described phenomenon for several viruses, including dengue, Ebola, respiratory syncytial virus, and HIV. ADE occurs when virus-antibody complexes engage Fc receptors (FcRs) and virus-specific receptors, enhancing infection under conditions of incomplete neutralization. The Coronavirus Immunotherapeutic Consortium (CoVIC) assembled a comprehensive dataset of functional properties for over 400 mAbs, enabling direct comparison of neutralization, Fc-mediated functions, receptor binding, and infection of immune cells. Infection rates in most primary human immune cell types were low, with modest increases observed for some mAbs. In contrast, macrophages were more susceptible to SARS-CoV-2 and exhibited substantial ADE with select mAbs. ADE was completely inhibited by FcR blockade and significantly reduced by antibody- or ceftazidime-mediated blocking of angiotensin-converting enzyme 2 (ACE2). Neutralization potency did not correlate with ADE, as both strongly and weakly neutralizing antibodies induced enhancement. Instead, ADE magnitude depended on an antibody’s ability to block spike protein binding to ACE2. Importantly, ADE resulted in productive infection with release of infectious virus. Evaluation of antibodies against the BA.1 (Omicron) variant revealed reduced or lost ADE for most mAbs, with increased ADE observed for several mAbs relative to the USA-WA1/2020 strain.

Authors

Natalia A. Kuzmina, Sivakumar Periasamy, Kritika Kedarinath, Keziah Hernandez, Caroline Atyeo, S. Moses Dennison, Kan Li, Daniel Bedinger, Sharon L. Schendel, Georgia D. Tomaras, Hanif Ali, Galit Alter, Erica Ollmann Saphire, Alexander Bukreyev

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Figure 3

The extent of ADE depends on binding to ACE2 and Fcγ receptors and less on epitope groups.

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The extent of ADE depends on binding to ACE2 and Fcγ receptors and less ...
(A) Proportion of mAbs from different epitope groups mediating low, moderate, and high ADE based on percentage relative to no mAb control. (B) Percentages of infected THP-1 cells treated with the selected mAbs of various epitope groups (shown under the graphs) and subgroups: 1, 2a, 2b, 2c, 2d, 3a, 3b, 4a, 4b, 4c, 5a, 5b, 5c, 5d, 6a, 6b, 7a, 7b, and 7c at 1 μg/mL. (C) Proportions of mAbs mediating low, moderate, and high ADE within epitope groups and subgroups described for B. (D) Proportion of mAbs from different epitope groups that cause no, moderate, or strong neutralization based on IC50. (E) Multivariable analysis reveals distinct clusters of mAbs with low, moderate, or strong ADE based on their ability to block ACE2 receptors, the FcγRIIa activity, neutralization IC50, ADE, and ADMP. (F) A loadings plot showing a relationship between ADE and ACE2, and between ADMP and FcγR activities. (G) Spearman’s correlation matrix of variables used for the principal component analysis.