Antibody-dependent enhancement (ADE) has been reported in several
virus infections including
dengue fever virus,
severe acute respiratory syndrome (SARS) and
Middle East respiratory syndrome (MERS)
coronavirus infection. To study whether ADE is involved in COVID-19
infections,
in vitro pseudotyped
SARS-CoV-2 entry into Raji
cells, K562 cells, and primary
B cells mediated by
plasma from recovered COVID-19
patients were employed as models. The enhancement of
SARS-CoV-2 entry into
cells was more commonly detected in
plasma from severely-affected
elderly patients with high titers of
SARS-CoV-2 spike
protein-specific
antibodies. Cellular entry was mediated via the engagement of Fc{gamma}RII receptor through
virus-
cell membrane fusion, but not by
endocytosis.
Peptide array scanning analyses showed that
antibodies which promote SARS-CoV-2 infection targeted the variable regions of the RBD domain. To further characterize the
association between the spike-specific antibody and ADE, an RBD-specific
monoclonal antibody (7F3) was isolated from a recovered
patient, which potently inhibited SARS-Cov-2 infection of ACE-2 expressing
cells and also mediated ADE in Raji
cells.
Site-directed mutagenesis the spike RBD domain reduced the neutralization activity of 7F3, but did not abolish its binding to the RBD domain. Structural
analysis using
cryo-electron microscopy (Cryo-EM) revealed that 7F3 binds to spike
proteins at a shift-angled pattern with one "up" and two "down" RBDs, resulting in partial overlapping with the receptor binding motif (RBM), while a neutralizing
monoclonal antibody that lacked ADE activity binds to spike
proteins with three "up" RBDs, resulting in complete overlapping with RBM. Our results revealed that ADE mediated by
SARS-CoV-2 spike-specific
antibodies could result from binding to the receptor in slightly different pattern from
antibodies mediating neutralizations. Studies on ADE using
antibodies from recovered
patients via
cell biology and structural
biology technology could be of use for developing novel
therapeutic and preventive
measures for
control of COVID-19
infection.