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SCIENCE science.org 7 JANUARY 2022 • VOL 375 ISSUE 6576 9A
s this year begins, the Omicron vari-
ant is smashing COVID-19 infection
records across Europe, North America,
Africa, and Australia. With massive
numbers of people infected or in quar-
antine, tens of thousands of flights
and trains have been canceled, and work and
schools disrupted. Earlier in the pandemic,
the frightful, near-vertical rise in cases would
have triggered stringent lockdowns. Not this
time: Many governments are banking on
early indications that vaccines still protect
against severe disease and that Omicron may
be a gentler variant.
It’s a risky bet, because scientists still
can’t predict Omicron’s ultimate toll. Initial
data from South Africa, Denmark, and the
United Kingdom suggest it causes less severe
disease, but they come with major caveats.
And even less severe cases can strain hospi-
tals already at the edge of their capabilities.
In a worrying sign, COVID-19 hospitalization
rates in the United States surged this week.
Virologists, molecular biologists, and
epidemiologists are biting their nails and
hoping cases will soon peak and begin to
fall. They are also working at top speed to
sort out the properties of the new variant.
Here are some of the key questions they are
trying to answer.How does Omicron differ from
previous variants?
Just 6 weeks after its discovery, it’s clear
the new strain behaves very differently
from previous ones. Early studies by sev-
eral groups hinted that Omicron replicates
less well in lung cells than other variants,
and two new studies have suggested a pos-
sible mechanism, based on how it enters
human cells.
SARS-CoV-2 has two entry routes. After
binding to ACE2 , a receptor protein on the
cell surface, virus particles can fuse with the
cell directly when another human protein
called TMPRSS2 cleaves the spike protein
on the virus’ surface. Alternatively, after
binding to ACE2, the virus can be swallowed
by the cell in a vesicle called an endosome.
The virus then escapes into the cell’s cyto-
plasm with the help of other spike-cleaving
proteins called cathepsins.
Early lab studies showed TMPRSS
cleaves Omicron’s spike protein less effi-
ciently than that of other variants, hamper-
ing the first, direct route. And in a preprint
posted last week, virologist Joe Grove of the
University of Glasgow and others showed
that blocking TMPRSS2 with the chemical
camostat inhibited pseudoviruses carrying
the spike of the Alpha or Delta variants in
cell culture, but not those carrying Omi-
cron’s. Conversely, blocking cathepsins witha compound named E64d inhibited viruses
carrying Omicron’s spike, but not Alpha’s
or Delta’s. Those data make “clear there’s
a very, very strong preference now for the
endosomal route,” Grove says. (Another
new preprint, by virologist Thomas Peacock
of Imperial College London and colleagues,
had similar findings.)
Some researchers argue Omicron may
spare the lungs and cause milder disease
because TMPRSS2 is more common on cells
in the lower airways, but there are few data
to support that, Peacock says. Cells infected
with Omicron may also be less likely to fuse
with neighboring cells to form large cells
called syncytia that might be a cause of se-
vere disease.
“For now, the combined data seem to
point in the direction of a less severe clini-
cal picture, possibly explained by changes
in how the viruses infect and which cell
types they infect,” says virologist Marion
Koopmans of Erasmus Medical Center.Could these changes in viral biology explain
why Omicron spreads so fast?
Perhaps. It’s possible they have shortened the
time between exposure and onset of symp-
toms, which studies suggest is only 3 days for
Omicron, down from about 4 days for Delta
and more than 5 for previous variants. This
is likely contributing to the steep rise inIN DEPTH
By Kai Kupferschmidt and Gretchen VogelCOVID-Omicron threat remains fuzzy as cases explode
Many countries break infection records; how much severe disease they will see is unclear
A temporary field hospital is constructed on the grounds of St. George’s Hospital in London on 30 December 2021 to handle an expected surge in severe COVID-19 cases.