2. Academic Validation
  3. SARS-CoV-2 antibody-dependent enhancement of infection depends on antibody binding to both ACE2 and Fc receptors

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

  • JCI Insight. 2026 Feb 23;11(4):e197773. doi: 10.1172/jci.insight.197773.
Natalia A Kuzmina 1 2,  Sivakumar Periasamy 1 2,  Kritika Kedarinath 1 2,  Keziah Hernandez 1 2,  Caroline Atyeo 3,  S Moses Dennison 4,  Kan Li 4,  Daniel Bedinger 5,  Sharon L Schendel 6,  Georgia D Tomaras 4,  Hanif Ali 7,  Galit Alter 3,  Erica Ollmann Saphire 6 8,  Alexander Bukreyev 1 2 9 10
Affiliations

Affiliations

  • 1 Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA.
  • 2 Galveston National Laboratory, Galveston, Texas, USA.
  • 3 Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
  • 4 Center for Human Systems Immunology, Departments of Surgery, Immunology, and Molecular Genetics and Microbiology and Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA.
  • 5 Carterra Inc. Salt Lake City, Utah, USA.
  • 6 Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, USA.
  • 7 Quadrucept Bio Ltd, Kemp House, London, United Kingdom.
  • 8 Department of Medicine, University of California San Diego, La Jolla, California, USA.
  • 9 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
  • 10 Center for Biodefense and Emerging Viral Infections, University of Texas Medical Branch, Galveston, Texas, USA.
PMID: 41729079 DOI: 10.1172/jci.insight.197773
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.

Keywords

Adaptive immunity; COVID-19; Immunoglobulins; Immunology; Virology.

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