Antibody-dependent enhancement of SARS-CoV-2 spike binding to human ACE2 receptor by virus neutralizing antibodies

Abstract

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated disease COVID-19 has caused over 275 million cases of illness and over 5 million deaths as of December 2021. The spike glycoproteins expressed on surface of the SARS-CoV-2 particle are the primary target of both vaccination and monoclonal antibody therapies. Widely reported evidence suggests that a subset of both naturally produced and synthetic antibodies (Abs) enhance infection, a phenomenon known as antibody-dependent enhancement (ADE). Recently, it has been demonstrated that the mechanism by which some Abs may elicit ADE is by enhancing the binding affinity of SARS-CoV-2 spike to its ligand - the human ACE2 receptor. Using in vitro spike-ACE2 binding assays, we identified two Abs which demonstrated ADE for spike/human ACE2 binding. Surprisingly, these binding-enhancing antibodies sufficiently neutralized SARS-CoV-2 pseudo-virus infection in human ACE2-knockin 293T cells, as well as live virus infection in Vero-E6 (non-human primate cell line) and Calu-3 (human cell line) cells in vitro. Furthermore, these receptor-binding enhancing antibodies significantly reduce but not enhance signs of SARS-CoV-2 infection in human ACE2-knockin mice, including viral replication and tissue pathology. Taken together, our data suggest a discrepancy between results of in vitro spike/receptor binding assay and virus neutralization assays for SARS-CoV-2 infection. Enhanced spike binding to host receptors is not a reliable measure of screening for ADE antibodies, but may be a mechanism by which virus neutralization is achieved in nature. This work was supported in part by grants from the National Institutes of Health (R01 AI151139, R56 AI146226 and P20 GM130555). W. Huang also received research support from MegaRobo Technologies Corporation.