From Carlyn Zwarenstein at Salon 10/9/24: "
All eyes on XEC: Why COVID sleuths are paying attention to this variant; Experts are keeping an eye on the XEC recombinant strain, which may cause trouble this winter"
"Stop me if you’ve heard this one before. A new variant of SARS-CoV-2, the virus that causes COVID-19,
suddenly breaks out like a horse from the gate, leaving the rest of the
race behind. This time, it’s a variant called XEC (“Zek”), which is a recombinant — the result of two variants joining forces.
“We controlled [the virus] a little bit initially, but then let it
rip, and once you have an uncontrolled spread, it does mutate. And also
it recombines, like when somebody has [been] infected with two different
things, like in this case KS.1.1 and KP.3.3 recombined to form this XEC
variant”, explained Dr. Raj Rajnarayanan, associate professor and
assistant dean at the New York Institute of Technology, in an interview
with Salon.
"Rajnarayanan, a computational biologist, has studied the repurposing
of old drugs for the treatment of viruses since the original SARS
outbreak of 2002-2004, and he’s closely following the rise of XEC, which
was recently added to the U.S. Centers for Disease Control and
Prevention (CDC)’s variant tracker. By the end of last month, XEC commanded an estimated 4.7% share of the total number of variants globally (and 6% in the US, with a wide margin of uncertainty), but unlike KP.3.1.1, which still holds a 36.9% share (58.7 in the US), XEC is on the way up, and fast.
“It might start becoming the top circulating lineage,” Rajnaranayam
said, predicting XEC will take the rest of October and early November to
gradually outcompete KP.3.1.1 in the United States, becoming the
dominant lineage over the winter 2024/25 season.
"Rajnarayanan doesn’t believe we need to worry about XEC in the sense
that it represents a substantially new form of SARS-CoV-2, as when the
first Omicron appeared on the scene with new symptoms and vast number of
new cases, spawning an entirely new branch on the virus’ evolutionary
tree. Jerome Adams, who was Surgeon General during the Trump
Administration and those terrible early days of the pandemic, sees
vaccination as part of a routine that, if kept up, can protect many of
us from the hospitalizations and deaths that COVID is still causing
regardless of the variant. And it can protect from the
increasingly-appreciated dangers of long COVID, in which the symptoms of the disease linger for months or even years.
“We’ve been through this literally dozens of times since 2020,” Adams
told Salon in a video interview. “There are going to continue to be
different variants out there. Sometimes they’ve going to be more
transmissible, sometimes they’ve going to be less, sometimes they’re
going to cause more [severe] disease, sometimes they’ve going to be less
severe. And we need to make sure we’re leveraging the tools that we
have available to be able to live with the virus, masking when it makes
sense, particularly in the midst of a surge, testing."
"Adams said it’s really important that people understand they can order four free at-home COVID tests, emphasizing to seek treatment if you test positive.
“Vaccines and ventilation are the big tools that I want people to
really think about,” Adams said. “And the new vaccines that are
available, the newly released vaccines from Moderna, Pfizer and from
Novavax.”
"Adams says that a big concern is the very poor recent uptake in
vaccination. Vaccines, which offer some short term protection against
transmission, are far more important in their ability to reduce severity
of acute COVID and incidence of long COVID. And in fact, as a
recombinant — which likely evolved
in an immunocompromised person infected for a very long time with the
two parent variants — XEC is a variation on a recent theme for which the
latest vaccines happen to be quite well-matched.
“We compared people who got the updated vaccine last year versus people
who did not, [and] we saw that there was a 60 plus percent, almost a 70%
decrease in hospitalizations and death in people who got the updated
vaccine last year,” Adams said. “There’s also increasing data out there
that shows that you may decrease your chances of long COVID by up to 70%
if you have an updated vaccine. So you’ve got something out there that
can really help protect people from both acute and long term problems,
but we’ve got very poor uptake, and I think it’s because, again, we keep
going through these surges, and it’s become kind of background noise to
a lot of people.”
"Adams notes that many, many Americans who are actually at high risk and
in need of updated vaccines (the original series no longer offer
significant protection in the face of newer variants) simply don’t see
themselves as being in a high risk category.
"We know that seven out of ten adults in the United States actually
have one or more risk factors for a negative outcome from COVID,” he
told Salon. These factors not only include things like cancer or immune
deficiency, but less obvious things like diabetes or pre-diabetes, high
blood pressure, respiratory issues — even obesity.
"Although typical symptoms of COVID infection have changed over time,
we have more tools — vaccines, drugs like Paxlovid and so on — than
before, and the risks associated with both acute disease and
post-infection symptoms remain substantially the same as they have since
we reached the point that most of the population had been exposed to
the virus’ spike protein, whether by infection with COVID or by
vaccination against it.
“And so one of the things we need to do is to help people understand
actually, the majority of U.S. adults have one or more risk factors for a
negative outcome from COVID, one, and a negative acute outcome. But
two, everybody is at risk for long COVID,” Adams stressed, even children.
Viral fitness
"Despite all that has remained constant, XEC has sparked interest
among experts, partly because it represents a bit of a mystery right
now. To understand that, we need to look a bit closer at what goes on in
viral evolution.
“There are three proteins we already always look at,” Rajnarayanan
explained. These include the spike protein; 3Cl, a protease or enzyme
necessary for viral replication (it’s the part of the virus that the
antiviral treatment Paxlovid targets); and a protein called N, which
stands for “nucleocapsid.”
"Ryan Hisner, a teacher and co-author of several papers on variants, told Salon that where XEC is most surprising is in the third of these: N, the nucleocapsid.
“I’m looking at [XEC’s spike protein], Hisner recalled, “and trying
to figure out, well, I don’t really see why it is even growing faster.
Usually if you have something come out and really start to spread
internationally, and grow and take over, there’s some pretty apparent
change that is conferring that kind of advantage to it. And it just
didn’t really seem like there was anything obvious. And so I started
looking through the rest of the genome.”
"As Rajnarayanan’s list makes clear, the famous spike protein isn’t the
only important part of SARS-CoV-2. The nucleocapsid protein is far and
away the most abundant protein in the virus. In coronaviruses, including
this one, N plays many roles, including allowing the virus to replicate.
But another vital role for the average N protein is to package up the
virus’ genetic material and tuck it inside the virion (the individual
virus being assembled) during active infection. It does this by holding
tightly to RNA, the single-stranded molecule that turns the genetic
information encoded in DNA into proteins.
"The original COVID variants were heavily phosphorylated — that is,
they contained a lot of phosphate atoms attached to different amino
acids making up the protein. All that phosphate reduced N’s ability to
bind RNA. This seemed to represent a trade-off: the virus was good at
evading immune responses from its hosts (humans but also other animals)
and at making copies of its genetic material, but not very good at
packaging them into new virions.
"At least, not so good compared to the more recent variants we’ve seen.
"That’s because, many variants ago (back in the days of B.1.1,
to be precise), the COVID virus came up with a new trick: mutations in
the nucleocapsid that truncated it, resulting in a shorter protein —
basically, a nucleocapsid protein that is missing half its length. This
shorter new nucleocapsid, called N* (pronounced “N star”) , was still
able to replicate efficiently but was also really good at packaging or
assembling virions, even though the missing part was the
highly-phosphorylated part that binds RNA.
"As Hisner put it in a Twitter thread, citing pre-print research
from Nobel Prize in Chemistry laureate Jennifer Doudna and others,
“with N*, the virus could have its cake and eat it too. It can go ahead
and phosphorylate N a bit more, boosting RNA synthesis, without having
to sacrifice as much assembly efficiency since little N* can take up the
slack on that front.”
"Variants with N* have typically produced higher viral loads and more
severe disease in patients. Hisner notes that early on in the pandemic a
common mutation that turned up in many variants right at or around the
usually-highly phosphorylated N3 region of the nucleocapsid likewise
decreased phosphorylation — just like the mutation that produced N* —
and that this also appeared to produce more severe disease.
"Clearly, reducing the phosphorylation of N and creating N* has
offered benefits that have allowed this mutation to flourish among
generations of variants.
“So N* was clearly a very advantageous mutation for almost the entire
pandemic,” Hisner said, “And now there’s this mutation that destroys
it, really."
"It started with the recent ancestor of XEC, KP.3.3, which exhibits a
mutation that undoes destroying the essential transcription region of N*
so the N* protein can’t be produced. Surprisingly, this variant has
done well, taking over in Japan, for example. And now KP.3.3’s
descendant, XEC, has the same little mutation and is surging in the U.S.
and elsewhere.
“It may be that somehow producing N* is now a detriment to the virus
where it used to be beneficial,” Hisner told Salon. In fact, with XEC’s
spike protein being pretty much the same as the currently leading
variant, the explanation for its surprising growth seems to be that this
time it’s a change in the nucleocapsid protein, not in the spike
protein, that is giving it a relative edge.
Playing the game
"About 450 Americans died of COVID
in the last week of September (down from over 1200 in the last week of
August). A further proportion — with wildly varying criteria and
estimates ranging from around 2% to over 10% — will end up with post-COVID symptoms,
which include long COVID but also things like heart attacks and
strokes, and new-onset diabetes in adults and children. Cognitive
impacts, which can be long-lasting or permanent, may occur after mild cases. Although COVID is known to have effects on the immune system and more infections correlate
with greater risk of post-viral symptoms, past infection is not yet
considered a pre-existing condition like others that increase the risk
of such symptoms.
"As a multisystemic vascular disease primarily transmitted through the
respiratory system, masks — especially N95-style respirator masks,
which use clever physics to filter particles as tiny as viruses — effectively prevent most transmission. However, cleaning air in shared spaces
by improving ventilation and using air filters is likely the most
effective way to make a dent in the availability of variants for
evolution to do its work on, while offering numerous other benefits for health and cognition.
“It frustrates me,” Adams said, “because honestly, you get around the
controversy of masking and of vaccinations and mandates when you just
make the air cleaner for everybody [...] I actually call it the biggest
missed opportunity of the pandemic.”
''Sure, XEC seems to have an advantage relative to other variants
around at the moment, which is driving its increasing share of cases.
But it’s no Omicron: unlike that gamechanger, XEC is prominent in a game
that we know all too well by now."
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