No Evidence for Human Monocyte-Derived Macrophage Infection and Antibody-Mediated Enhancement of SARS-CoV-2 Infection

Abstract

Vaccines are essential to control the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and to protect the vulnerable population. However, one safety concern of vaccination is the possible development of antibody-dependent enhancement (ADE) of SARS-CoV-2 infection. The potential infection of Fc receptor bearing cells such as macrophages, would support continued virus replication and inflammatory responses, and thereby potentially worsen the clinical outcome of COVID-19. Here we demonstrate that SARS-CoV-2 and SARS-CoV neither infect human monocyte-derived macrophages (hMDM) nor induce inflammatory cytokines in these cells, in sharp contrast to Middle East respiratory syndrome (MERS) coronavirus and the common cold human coronavirus 229E. Furthermore, serum from convalescent COVID-19 patients neither induced enhancement of SARS-CoV-2 infection nor innate immune response in hMDM. Although, hMDM expressed angiotensin-converting enzyme 2, no or very low levels of transmembrane protease serine 2 were found. These results support the view that ADE may not be involved in the immunopathological processes associated with COVID-19, however, more studies are necessary to understand the potential contribution of antibodies-virus complexes with other cells expressing FcR receptors.

Antibody-Dependent Enhancement of SARS-CoV-2 Infection Is Mediated by the IgG Receptors FcγRIIA and FcγRIIIA but Does Not Contribute to Aberrant Cytokine Production by Macrophages

“…ADE of infection of SARS-CoV-2 was also identified in primary macrophages ( Fig. 3A ), indicating that hACE2 is expressed on monocyte-derived macrophages, as well as FcγRs, which has been reported previously ( 12 ).…”

“…ADE of infection occurs with a variety of viruses, including dengue virus, respiratory syncytial virus, and influenza virus, as well as the coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) ( 5 , 6 ). Several studies have been performed to investigate whether SARS-CoV-2 infection induces ADE of infection ( 11 , 12 ), and ADE of SARS-CoV-2 infection was observed in a study of convalescent-phase-plasma therapy ( 12 ). While FcγRIIA was reported to mediate ADE of SARS-CoV-2 infection in that study, the precise mechanism was not fully elucidated.…”

Inflammasome activation at the crux of severe COVID-19

“…Indeed, antibody depletion of patient plasma and blocking antibodies to the monocyte Fc receptor FcγRIIIa (also known as CD16) largely abrogated monocyte infection. While this finding contradicts the finding of another study 122 , it is supported by the observation of increased afucosylated antiviral antibodies seen in patients with severe COVID-19 (refs 123 , 124 ). The Fc domain of IgG antibodies contains a conserved N-linked glycan, and IgG lacking core fucosylation at this glycan has higher affinity for FcγRIIIa.…”

Accelerated Development of COVID-19 Vaccines: Technology Platforms, Benefits, and Associated Risks

“…On the lines of studies performed on SARS- and MERS-specific vaccines, challenge experiments using NHP could be particularly suitable for detecting an ERD risk. At present, there is no evidence that ADE is involved in immunopathological processes in the context of COVID-19 [ 23 ], but the impact of emerging variants on ADE is still unclear.…”