XBB.1.5 shows we’re thinking about covid variants all wrong. Here’s a better way.

Gone are the days of single variants sweeping the globe. We need to adopt a more holistic framework.

When it comes to watching the coronavirus’s evolution, the world is no longer tuned in to the same show.

The first two years of the pandemic saw one major variant after another spring up and sweep the globe, like a quick change of a television channel. The original virus gave way to alpha, then delta and then omicron – with each version of the virus usurping the last. But over the last year, the explosion of omicron subvariants has amounted to a global TV playing hundreds of channels, with no one version dominating worldwide (or even across the same continent).

One of these omicron offshoots might barely register in one place but cause a major spike in illness elsewhere, as happened with BA.2.75 in India. Another might seem inconsequential until it recombines with a cousin to produce a new highly transmissible and immune-evasive variant, such as XBB.1.5, which is now taking off in the northeastern United States.

The pandemic is no longer a succession of clearly dominant players but a roiling mix of many. Nor does the arrival of a new major variant in a country or region warrant the same level of preparation or fear, in many cases. In the United States, vaccines, boosters and prior waves of infection with omicron and its offspring have bolstered immunity at the population level, and we have treatments like Paxlovid and remdesivir for the most vulnerable. And yet this roiling mix is still exacting a significant toll on the country, with some variants playing a bigger role than others.

But the popular conception of variants hasn’t kept up with this change. When new ones emerge, they’re often quickly met with either blaring sirens or silent shrugs — both reactions are harmful in their own ways. The rapid channel flipping as variants pop up leaves much of the public numb to the impact of the virus’s continued evolution and increasingly less willing to respond with collective measures like mask-wearing and social distancing when a serious threat does emerge.

“The immunological history of a population is now much more complicated than it was at the beginning,” said Sam Scarpino, an evolutionary biologist at Northeastern University. “It’s just a lot harder to reason through what may or may not happen with any new variant that shows up.”

A more varied immune landscape

When SARS-CoV-2 first spilled into humans, we were all blank slates, immunologically speaking. Without preexisting defenses, any human the virus encountered looked the same.

In that homogenous landscape, the main way a new mutation could differentiate itself was by increasing transmissibility. A variant that spread faster in one population could likely do the same in another since no one had immunity. Of course, many other factors, from demographics to seasonality, also shaped any location’s experience with those early variants. But “the first part of the evolutionary trajectory is going to be about the intrinsic properties of the virus,” said Scarpino.

Now, just about everyone on the planet has some immunity, either through vaccination or infection. But the nature of that immunity depends on myriad factors that change over time. “I know people who haven’t gotten covid and some who’ve had it four times, some who’ve been infected and gotten boosted, others who didn’t get boosted, people that had delta but not omicron, omicron but not delta,” said Scarpino.

On a larger scale, differences in how countries have dealt with the pandemic create regional variation. China, which is just lifting its zero-covid policies, looks a lot different to the coronavirus than Sweden, which took a more lax approach beginning in 2020. “All those interactions matter in terms of the probability of getting infected,” he said.

That varied and changing landscape means there are many more ways for the coronavirus to make a living, so to speak. That’s “part of the reason why there are so many more variants out there,” said Scarpino. It also makes evaluating or predicting the impact of any given variant more difficult.

Take BF.7, which split off from the omicron BA.5 lineage that caused many surges this summer across Europe and the United States. BF.7 has mutations that help it dodge antibody responses (like those spurred by prior infection or vaccination) but has been relatively quiet around the world. But in China, BF.7 is driving a surge in infections among a population with almost no exposure to any version of covid, threatening to overwhelm the country’s healthcare system.

“Context matters,” said T. Ryan Gregory, an evolutionary biologist at the University of Guelph. “You can have a mutation that is totally irrelevant in one environment, massively successful in a different environment and detrimental in a third environment,” he said. Drawing conclusions about whether a variant will cause a spike in illness or death based on a snapshot in time just doesn’t work anymore. “This expectation of a sharp peak caused by one variant is really distorting our understanding,” he said.

It can also blind us to the actual ongoing impact of variant evolution.

“There’s this idea that unless something is surging, causing a huge number of hospitalizations on par with the first waves, it’s not something to worry about,” said Gregory. But these omicron offshoots have been killing between 300 and 400 people each day in the United States since the end of spring and leaving scores more with long covid and other complications. Omicron and its subvariants caused Canada’s deadliest year of the pandemic yet in 2022. Gregory and others argue that we must ditch the old way of looking at variants as static entities that can be assessed with a snapshot and instead take on a more global and dynamic perspective.

“We always want to boil this down to something simple, but it’s time to be holistic rather than reductionist,” he said. “Reductionism worked OK while it was a simple system, but it’s not simple anymore, and it’s causing us to really lag behind what’s going on.”

A more holistic view

A more holistic view starts with a better global surveillance system that can monitor this more dynamic phase of the pandemic, sequencing the genetic material of viral samples to track new variants as they emerge and spread. Genomic surveillance is much better than it was in 2020, but there are worrying signs of complacency — submissions to GISAID, a global genomic data repository, are down 90 percent compared to last year.

“We need to be collecting that data and looking at trends over time,” said Pavitra Roychoudhury, director of covid-19 sequencing at the University of Washington School of Medicine’s virology lab. Such data helps scientists identify mutations that might prove problematic and track how those mutations play out in different contexts.

“That’s what we’re doing with XBB.1.5, looking to see how its proportion [relative to other lineages] changes over time,” Roychoudhury said.

Experts’ views of the threat posed by XBB.1.5 are in flux. Key mutations that increase the variant’s ability to bind to cells and replicate worried scientists in December. It seemed to be taking off by late December, when the Centers for Disease Control and Prevention reported XBB.1.5 represented 41 percent of new cases nationwide, nearly double the figure from previous week. Later, however, that estimate was revised downward to less than 30 percent.

Such changes are normal. They also highlight how difficult it is to get a clear picture of a dynamic situation. It will take even more time for scientists to determine whether XBB.1.5 causes more severe illness or is more likely to lead to long covid.

There’s no simple way to communicate this complex and dynamic situation, said Roychoudhury, especially with so many variants in the mix. That leaves public health officials with a major challenge. If they raise too many alarm bells, the public may grow numb. If they undersell a threat, they risk missing the chance to act, or at least alert those at higher risk of serious illness, before it’s too late.

Roychoudhury advocates being explicit about what’s currently known and unknown about a given variant and what officials will continue to monitor.

“We can’t be alarmist,” she said, but officials should be clear when a new variant is outcompeting others while also communicating the context — seasonality, changes in behavior, vaccination rates, overall population immunity — that impacts the spread. “That’s step one; then we’re going to understand how it’s evading existing protection and see what kind of impact it has on hospitalizations and so forth,” she said. That can inform whether additional protective measures are warranted. “Breaking that down is better than panicking at the outset when you see a variant emerge.”

Hyper-focusing on variants can also encourage short-sightedness, a sense that we just have to get through this surge and then we’ll be OK. Time after time that view has been proven wrong.

A more holistic view of variants acknowledges that the virus will continue evolving, continue finding ways of getting around that hard-won protection. That doesn’t spell total doom — the virus likely can’t make a leap so big that we’re back at square one. Over time, the global build-up of immunity may translate to less severe infections, on average. But that’s no guarantee, and the more we allow the virus to evolve, the more opportunities we give it to surprise us.

“Ultimately, if there’s unmitigated transmission, there will be a lot of cases. And if there’s a lot of cases, there will be a lot of evolution,” said Gregory. “That’s just basically it.”

Correction

An earlier version of this story misstated that 300 to 400 people have been dying every week, instead of every day, from covid in the United States since the end of spring. This version has been updated.

Thanks to Brett Zach for copy editing this article.

Jonathan Lambert

XBB.1.5 shows we’re thinking about covid variants all wrong. Here’s a better way.