Understanding SARS-CoV-2 evolution and host
immunity is critical to
control COVID-19 pandemics. At the core is an
arms-
race between
SARS-CoV-2 antibody and
angiotensin-converting enzyme 2 (ACE2) recognition, a function of the
viral protein spike.
Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, with the effect of
mutation synergy still incompletely understood. We engineered 25 spike-pseudotyped
lentiviruses containing individual and combined
mutations, and confirmed that E484K evades antibody neutralization elicited by
infection or
vaccination, a capacity augmented when complemented by K417N and N501Y
mutations.
In silico analysis provided an explanation for E484K
immune evasion. E484 frequently engages in interactions with
antibodies but not with ACE2. Importantly, we identified a novel
amino acid of concern, S494, which shares a
similar pattern. Using the already circulating
mutation S494P, we found that it reduces antibody neutralization of convalescent and post-
immunization sera, particularly when combined with E484K and N501Y. Our
analysis of synergic
mutations provides a landscape for hotspots for
immune evasion and for targets for
therapies,
vaccines and diagnostics. One-Sentence SummaryAmino
acids in
SARS-CoV-2 spike
protein implicated in
immune evasion are biased for binding to
neutralizing antibodies but dispensable for binding the host receptor
angiotensin-converting
enzyme