60 Scientific American, May 2022among other variants. Those changes to its anatomy gave it new
and surprising abilities. If Delta is the brute-force Hulk variant,
think of Omicron as the Flash—masked and wicked fast.
Here we explore four ways that the variant has physically
changed. Three of those alterations helped this version of
the virus evade our immune systems and become more infectious,
whereas the fourth may have led it to produce more mild disease.
It wore a disguise. What made Omicron so transmissible,
most evidence indicates, is a single, potent mechanism: among
the variants, Omicron had an unparalleled ability to hide from
the immune system.
During infection, fist-shaped clumps of amino acids atop the
coronavirus spike called receptor-binding domains (RBDs) grab
onto a protein on the outside of some human cells: the ACE2
receptor. To prevent that ill-fated attachment, the immune sys-
tem creates antibodies—Y-shaped proteins induced by prior infec-
tion or vaccination—that recognize an RBD and stick to it like
Velcro, getting in the way so the virus cannot link up with ACE2.
In previous variants, one, two or maybe three amino acids on
RBDs were mutated, altering each RBD just enough to prevent
some but not all antibodies from recognizing it. But Omicron
harbored 15 RBD mutations, many on prime antibody-binding
sites, forming an elaborate disguise to avoid many more anti-
bodies. It was as if the virus donned a full-blown Mission: Impos-
sible –style latex mask to change its face. “There are just so many
mutations and so many new ones,” says Matthew McCallum, a
biochemist at the University of Washington.
In an analysis published in the journal Science, McCallum,
with his laboratory head David Veesler and their colleagues,
showed a consequence of this dramatic transformation: only one
of eight antibody treatments for COVID used in hospitals—which
are based on natural antibodies—still bound effectively to RBDs.
Other research has shown that mutations on RBDs and a second
site called the N-terminal domain enable the virus to avoid anti-
bodies gained by vaccination or infection. Thanks to Omicron’s
convincing disguise, the variant had little to slow it down, and
it spread with lightning-fast speed. Vaccines, however, still
warded off serious illness, especially with booster shots.
It stabilized. When Omicron drastically altered its spike to
hide from the immune system, those changes eliminated some
chemical residues the spike needed to
attach to ACE2. But other mutations
compensated: RBDs formed new chemi-
cal bridges to still effectively bind to the
protein, according to another study in
Science. “It clearly lost some residues
important for binding, but it made them
up with other interactions,” says Subra-
maniam, who was the senior author
of the paper.
The spike protein also became stur-
dier. In other variants, two subunits
within the spike, S1 and S2, are loosely
connected. This allows them to split
apart quickly so the spike can bury itself
in a human cell when the virus encoun-
ters one. The downside of this delicate
arrangement, however, is that many
spikes split prematurely, before getting
close to a cell. Once asunder, the spikes
can no longer help the virus attach.
Mutations in Omicron led to slim
molecular bridges that hold the subunits
together better, according to several
studies. One was published in the Jour-
nal of Medical Virology, and the others
were released as preprint papers that
have not yet been formally reviewed by
other scientists. “This virus has really
protected itself from prematurely trig-
gering,” says Shan-Lu Liu, author of one
of the papers and director of the Viruses
and Emerging Pathogens program at the
Ohio State University. “When the virus
is in the right place at the right time, it
can be triggered and get into the cell, but
not prior to that.”
It slipped in the side door. Across
previous variants, there was one con-Bridge mutationsInfected cellIntact spike
Split spikeOlder variantOmicronSpike Stability
The spike protein has two subunits that need to separate as the virus infects a cell.
In earlier variants, they were delicately attached and frequently split too early.
Some of Omicron’s mutations form extra molecular bridges between the two spike
subunits, known as S1 ( light blue ) and S2 ( dark blue ). The bridges keep the subunits
from separating prematurely. A greater number of intact spikes make it easier for
Omicron to infect more cells.