All eyes on XEC: Why COVID sleuths are paying attention to this variant

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.

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“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.