The winter holidays are fast approaching, and once again a new SARS-CoV-2 variant is likely to crash some festivities.
XEC, the up-and-comer among circulating SARS-CoV-2 viruses, arose from the recombination of 2 other variants. Fortunately, all 3 are descendants of the original Omicron virus and are closely related to the variants targeted by the latest COVID-19 vaccines, which are JN.1 and KP.2.
“They’re all really, really close,” said Nicole Doria-Rose, PhD, chief of the Antibody Immunity Section at the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center. XEC has only 4 amino acid changes from both JN.1 and KP.2, she explained.
Recombination is thought to occur when a single individual, usually someone who is immunocompromised, becomes infected with more than one SARS-CoV-2 variant at the same time, explained epidemiologist Bill Hanage, PhD, associate director of the Center for Communicable Disease Dynamics at the Harvard T.H. Chan School of Public Health.
First detected in Germany on August 7, XEC was deemed a “variant under monitoring” in late September by the World Health Organization (WHO), which means that public health authorities should keep an eye on it in case it becomes a bigger threat than other circulating variants.
The timing and location of the initial identification of XEC suggest it might have arisen in a fan attending the EURO 2024 soccer tournament, held from mid-June to mid-July in stadiums around Germany, Hanage noted. Although “we’ll never know exactly where it happened,” he said, “events like that certainly provide opportunities for new variants to get established.”
Or, perhaps, XEC was born at the Paris Olympics, which began in late July, Doria-Rose pointed out, echoing Hanage: “We’ll never know.”
No matter where it was born, XEC has taken off around the world. In the week ending October 13, the variant constituted about 17% of SARS-CoV-2 sequences globally, up from about 9% in the week ending September 22, according to the WHO. Between those 2 periods, XEC increased in the Americas, Europe, and the Western Pacific, the WHO reported.
In the US, the national genomic surveillance system first sequenced XEC during the 2-week period ending August 31, at which time it represented 1% of variants sequenced. By the 2-week period ending November 9, the Centers for Disease Control and Prevention (CDC) estimated that XEC comprised 28% of circulating variants, up from 17% the previous 2 weeks.
Although XEC might not be increasing as quickly as the CDC estimates suggest, “[i]t’s going to make up substantial amounts of the transmission we see in the coming weeks,” Hanage predicted. “I think there’s a good chance it is going to become the dominant variant.”
Fortunately, XEC is similar enough to other circulating variants that it’s not expected to cause worse symptoms or undermine the latest COVID-19 vaccines’ ability to prevent severe disease. “There’s no evidence that it’s making people sicker,” Hanage said.
In previous years, COVID-19 has surged after winter holiday get-togethers. But because of the “huge” COVID-19 summer wave, “it’s hard to know when the winter wave is going to happen,” said Helen Chu, MD, MPH, a professor of medicine and allergy and infectious diseases at the University of Washington.
More Variants, Less Surveillance
XEC is not the first recombinant SARS-CoV-2 variant, and it’s unlikely that it will be the last. Predecessors include XBB; the 2023-2024 COVID-19 vaccine targeted an XBB spinoff, XBB.1.5.
Recombination “helps the virus mutate faster,” Doria-Rose explained.
And that can be advantageous by increasing transmissibility and immune evasion, virologist Kei Sato, PhD, a professor at the Institute of Medical Science at the University of Tokyo, pointed out in an email.
Variants born of the recombination of 2 or more variants generally emerge when multiple SARS-CoV-2 lineages are circulating at the same time, which has become increasingly common, noted a recent article on the subject. It’s thought that recombination of different coronaviruses played a role in the origin of SARS-CoV-2, according to the authors, some of them California Department of Public Health scientists.
“Recombinant variants…often have unknown impacts on transmission, immune escape, and virulence in the early stages of emergence,” they wrote. By the end of 2022, 60 recombinant SARS-CoV-2 variants had been designated; some traveled the world, while others remained local clusters.
But detecting, monitoring, and responding to new recombinant variants have become more challenging, given such factors as decreasing sequencing worldwide since public health emergencies expired, the authors concluded.
“We’re just not spending the money on it anymore,” Doria-Rose said of genomic surveillance.
A major event in the evolution of the Omicron variant, first identified in November 2021, has occurred pretty much every year, Sato pointed out.
“Not sure the big event in 2024 is XEC yet,” he wrote in his email.
On November 6, he and coauthors published a research letter in The Lancet about XEC’s virological characteristics.
The authors estimated XEC’s effective reproduction number, which refers to the number of susceptible people who can be infected by a single individual. In the US, XEC—the product of JN.1 offspring KS.1.1 and KP.3.3—has an effective reproduction number that is 13% higher than that of KP.3.1.1, the most predominant SARS-CoV-2 variant in the world as of early November. That suggests that XEC could potentially outcompete other variants, including KP.3.1.1, Sato’s team wrote.
They assessed XEC’s infectivity and immune evasion in laboratory experiments using SARS-CoV-2 pseudoviruses engineered to bear the spike proteins of KP.3, KP.3.1.1, or XEC.
In one experiment, they found that KP.3.1.1 and XEC had statistically significantly higher infectivity of cells in a dish than KP.3.
In the other experiment, they assessed neutralizing antibody titers in serum samples exposed to the SARS-CoV-2 pseudoviruses. The sera came from patients who’d recovered from XBB.1.5, KP.3.3, or JN.1 infections, most of whom had received at least 2 COVID-19 vaccines but had not yet gotten the latest version. The researchers found that XEC exhibited higher immune evasion than KP.3.
“I think the level of neutralization activity by natural infection is decreasing,” Sato told JAMA Medical News. In other words, he said, people shouldn’t think that SARS-CoV-2 infections alone will generate sufficient immune responses to protect against reinfection.
“I assume that the induction level of neutralization antibodies by vaccine would be greater than that of natural infection,” Sato continued, adding that he and his collaborators are now studying neutralizing antibodies in sera from individuals who received the 2024-2025 COVID-19 vaccines.
Updated Vaccines Still Doing Their Job
When the US Food and Drug Administration’s vaccine advisory committee met in late June to make recommendations about the 2024-2025 COVID-19 vaccine, no one had ever heard of XEC, which likely didn’t even exist at that point.
Even so, because XEC is yet another JN.1 descendent, it’s likely that all the available 2024-2025 COVID-19 vaccines—which target either JN.1 or its offspring KP.2—will provide protection against severe disease and death, noted Chu, a member of the CDC’s Advisory Committee on Immunization Practices. The antiviral treatment nirmatrelvir plus ritonavir (Paxlovid) still appears to be effective against XEC infection, she added.
Moreover, the JN.1 and KP.2 vaccines “are all way better than XBB would have been” against XEC, said Doria-Rose, referring to the 2023-2024 XBB.1.5 vaccines.
That is, if people get them.
Data posted by the CDC on November 8 show that in about the first 2 months after the latest COVID-19 vaccines became available, only about 17% of adults had received one. The proportions were lower in children, about 8%, and higher in people aged 65 years or older, about 38%.
Although COVID-19 mortality has been declining, people are still dying from the disease. As of November 7, COVID-19 was listed as the cause or a contributing factor for more than 40 000 US deaths this year, based on CDC provisional data.
For most healthy people, COVID-19 has become a milder illness, but it still leads to more hospitalizations than influenza and is especially dangerous in older adults and in people with compromised immune systems, Chu pointed out.
With that in mind, Hanage noted, “I will be more conscious about getting exposed if I’m going to visit my elderly father. That’s a situation where I would think about it more carefully.”
Published Online: November 22, 2024. doi:10.1001/jama.2024.24481
Conflict of Interest Disclosures: Dr Hanage reported serving as a paid scientific advisor to Merck Vaccines, Shionogi Inc, Pfizer, and Biobot Analytics, a company in which he holds stock options. Dr Chu reported receiving personal fees from AbbVie, Vindico, Ellume, Medscape, Merck, Clinical Care Options, Cataylst Medical Education, Vir, Pfizer, and Prime Education. Dr Sato reported receiving consulting fees from Moderna Japan and Takeda and honoraria for lectures from Moderna Japan and Shionogi. No other disclosures were reported.
