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

## TL;DR

Some SARS-CoV-2 antibodies can enhance infection by binding to ACE2 and immune cell receptors, leading to increased virus spread.

## Contribution

The study reveals that ADE of SARS-CoV-2 depends on antibody binding to both ACE2 and Fc receptors, not just neutralization potency.

## Key findings

- ADE was significantly reduced by blocking ACE2 or Fc receptors.
- Macrophages showed higher susceptibility to ADE compared to other immune cells.
- ADE magnitude depends on an antibody's ability to block spike protein binding to ACE2.

## 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.

Some of antibodies induced by SARS-CoV-2 facilitate enhancement of infection which depends on antibody binding to both ACE2 molecule and Fc receptors on immune cells.