Update (May 5, 2022): A preprint currently under review at Nature suggests that the Omicron variant may be as severe as previous variants when variables such as vaccination status are controlled for, according to Reuters.

When the Omicron variant of SARS-CoV-2 first began to spread rapidly and outcompete other variants in late 2021, it quickly became apparent that the variant was quite different than those that came before it.

Unlike Delta, which emerged in December 2020 and was linked to a massive surge in hospitalizations and deaths last year, Omicron didn’t seem to be as dangerous on the scale of individual infected people. Yet hospitals, clinics, and intensive care units have still filled up with patients as the tally of new cases and hospitalizations, currently at more than 145,000 in the United States, shattered records day after day, in no small part because a series of mutations in the virus’s spike protein render vaccines far less effective at stopping infection than they have been with previous variants. The parallel spike in deaths that lagged shortly behind case numbers in other surges is now starting to emerge.

Meanwhile, record numbers of children are being hospitalized with COVID-19, according to The New York Times, and the number of new infections reported per day continues to skyrocket. On Wednesday (January 12), the 14-day average tally of new daily cases in the US surpassed 780,000.

As Omicron continues to spread, several questions remain about how and why it differs from other variants in terms of both disease outcomes and transmissibility. Some findings, such as clinical reports indicating that Omicron patients fare better than those with other variants and research suggesting that Omicron doesn’t target tissues associated with worse disease outcomes, offer encouraging signs. But whether that makes Omicron “mild” is, experts say, less clear.

“I think it’s pretty clear Omicron causes less severe disease than the Delta variant, but that’s not saying much,” University of Western Australia epidemiologist and biostatistician Zoë Hyde writes in an email to The Scientist. “We know that Delta was more than twice as severe as the original strain, and if Imperial College is right to say that Omicron is about 40-45% less likely to put people in hospital [than Delta was], we’re back to 2020 but with a more contagious strain.”

Oversimplified narrative

A now-famous report from Imperial College London published on December 22 found that COVID-19 patients infected with Omicron had a 20 to 25 percent reduced risk of hospitalization compared to those with Delta, and a 40 to 45 percent reduced risk of a hospital stay that lasted one or more days—which the researchers used as an indicator of severe cases.

That discovery helped fuel a narrative, popular in the media, that Omicron is mild. But Omicron was first detected in South Africa, a country with a relatively young population of people who are largely either vaccinated, already recovered from COVID-19, or both. That made it hard, experts tell The Scientist, to tell whether Omicron’s severity was really a step back from Delta’s, or if, instead, any new variant emerging this late into the pandemic would seem less severe due to the acquired immunity and clinical knowledge that’s built up over time.

Researchers who spoke to The Scientist tentatively agreed, with varying amounts of confidence, that Omicron is in fact causing relatively fewer cases of severe disease than the Delta variant—a conclusion that’s been supported by several different preprint reports. But varied levels of vaccination, hospital capacity, and other population-level factors across different countries and regions complicate the situation.

The reports from South Africa about a milder course are not necessarily applicable to patients with chronic conditions and the immunocompromised.

—Sandra Ciesek, The German Center for Infection Research

“I still think that the single biggest factor causing that lower per-case severity is likely to be widespread immunity among the majority of those who are infected, with slightly lower intrinsic severity of the virus a likely additional factor,” Roby Bhattacharyya, an infectious disease expert at Massachusetts General Hospital and the Broad Institute of MIT and Harvard, tells The Scientist over email. “But I still think this gets conflated in most popular messaging—understandably, since it’s pretty nuanced—such that most people walk away saying ‘Omicron is milder’ when I think the truth is, any SARS-CoV-2 virus infecting this mix of people would look milder.”

In short, factors such as vaccination may have blunted Omicron’s blow, making it seem less severe than the variants that emerged before COVID-19 vaccines were widely deployed. That means that the Omicron variant shouldn’t be underestimated—a point recently underlined by World Health Organization Director-General Tedros Adhanom Ghebreyesus, who on January 6 said that it’s more appropriate to say Omicron is “less severe” than other variants than to call it “mild.”

“Just like previous [COVID-19] variants, Omicron is hospitalizing people and it is killing people,” Tedros added.

With so much pre-existing immunity to SARS-CoV-2, we won’t know whether and to what extent Omicron is truly milder than previous variants “until we have big enough numbers on the truly unvaccinated,” says Sumit Chanda, an infectious disease expert at the Sanford-Burnham Medical Research Institute who’s worked on COVID-19 therapeutics.

Those who don’t have any prior immunity—whether that’s because they haven’t been vaccinated or infected or as a result of having disabilities, chronic illnesses, or conditions that leave them immunocompromised—are more likely to face severe symptoms and death as a result of an Omicron infection, researchers tell The Scientist.

“The reports from South Africa about a milder course are not necessarily applicable to patients with chronic conditions and the immunocompromised,” Sandra Ciesek, a virologist at Goethe University and the German Center for Infection Research, writes in an email to The Scientist. “I fear that, even with Omicron, we will see severe courses especially in these patient groups.”

Zoom out from the scale of an individual patient, and the sheer number of Omicron infections and especially reinfections means that Omicron must still be taken seriously. According to a preprint from December 2, Omicron carries a vastly increased risk of reinfection compared with previous SARS-CoV-2 variants.

“I think there’s genuine good news about both intrinsic severity appearing to be slightly lower and immunity holding decently well against severe disease, far better than it is against infection,” Bhattacharyya says. “I just find myself a bit concerned about the oversimplified narrative that ‘Omicron is milder,’ or even worse, ‘Omicron is mild.’ The nuance matters here, I think.”

Public health experts note that a somewhat less-severe but far-more-transmissible disease that still puts people in the hospital can lead to dire situations at healthcare facilities, which are already facing worker burnout, overcrowding, and shortages. This is already playing out in the US and elsewhere, where patients who need surgeries and other medical procedures are being forced to wait until there’s room.

“If you do get sick and you’re boosted, there’s not going to be a huge chance you end up in a hospital,” Chanda tells The Scientist. “But if you do, it would be nice if there was a bed for you and therapeutics that could help you.”

Why so different?

Some clues have begun to emerge about why Omicron is more transmissible, and possibly less deadly, than its predecessors. A growing body of research suggests that Omicron’s numerous mutations—it has 30 in the spike protein alone—make the variant spread more rapidly, infect people more readily, and evade existing immunity far better than other variants.

“The facts on the ground have changed with Omicron,” Chanda tells The Scientist. “It is a different virus than what we made the vaccine to, and we need to adjust what our conclusions and expectations are of the vaccines and the booster.”

Because the vaccines explicitly target the spike, an immune system primed by vaccination has a harder time stopping Omicron than other variants from infecting host cells. Thus, a vaccinated person who’s exposed to the Omicron variant is more likely to experience symptoms than they would if they had been exposed to a variant the immune system was better trained to attack, Chanda says. Research shared online earlier this month concluded that the difference between Omicron and all earlier variants of concern is so great that vaccines ought to be updated specifically to target the new variant. (Both Moderna and Pfizer have said they plan to release new, Omicron-specific vaccines, but experts emphasize that the ones available today are far from worthless, largely preventing severe and fatal cases of COVID-19, even with Omicron.)

It’s not clear how Omicron’s many differences from other variants might translate into a reduction in severity, but animal models and findings that Omicron infects different tissue than Delta offer some clues. In preprint research shared online on December 28, James Stewart, a molecular virologist at the University of Liverpool, and colleagues found that mice have lower viral loads when they’re infected with Omicron than with other variants. Despite this somewhat counterintuitive result, Stewart says that his mouse model has been highly predictive of clinical outcomes for other variants, and that Omicron wouldn’t necessarily need to result in a high viral load in order to spread as rapidly as it has.

However, Stewart concedes that the reduced viral load in Omicron cases is “really a bit of a mystery,” and that “the data’s really not there” to explain why it happens. That said, Stewart speculates that this reduction could be related to how the Omicron variant seems to replicate rapidly in the upper respiratory tract but doesn’t really spread to the lungs or beyond.

See “Omicron Propagates 70 Times Faster than Delta in Bronchi: Study

Experts, Stewart included, have hypothesized that Omicron’s preference for infecting the bronchi over lung tissue may explain the reduced severity of COVID-19 symptoms that patients seem to experience compared with other variants. “It’s replicating in places that cause less damage,” Chanda tells The Scientist. Infecting the bronchi is “not great for [reducing] transmission, but it’s not going to really cause acute pathophysiology here.”

A growing number of other recent preprint studies support that hypothesis. Ciesek adds that her own lab has published a preprint showing that Omicron is less efficient than Delta at preventing the body’s interferon response, in which infected cells release these proteins to cue greater antiviral activity among their neighbors, suggesting that the immune system can fight off Omicron better than Delta once it’s been infected. “All of these data may fit with the clinical observation that Omicron causes less lethal disease in the lung,” Ciesek writes. 

I just find myself a bit concerned about the oversimplified narrative that ‘Omicron is milder,’ or even worse, ‘Omicron is mild.’ The nuance matters here, I think.

—Roby Bhattacharyya, Broad Institute of MIT and Harvard

However, she adds that the best indication of disease severity would be a study of outcomes among unvaccinated Omicron patients. In that regard, Ciesek feels that the Imperial College London study, which separately analyzed the hospitalization risk of vaccinated and unvaccinated patients, still paints the best picture of outcomes for both. The report, which compared the risk of hospitalization due to Omicron and Delta among people with various combinations of vaccine doses, found that Omicron caused 50 percent less hospitalization than Delta had among those with two shots of an mRNA vaccine, and 26 percent less hospitalization among unvaccinated individuals.

Bhattacharyya shares a similar sentiment about the study, though he adds that the situation is changing so rapidly that the data, just a few weeks old, are quickly becoming outdated. “I'm eagerly awaiting an update on that analysis, because I think the next round of numbers will really teach us a lot about intrinsic severity of Omicron in each group of people (non-immune; immune from prior infection; immune from various prior vaccinations; boosted; etc), which will be far more illuminating than population-level metrics,” he tells The Scientist over email.

Transmissibility versus severity—fate or coincidence?

Beyond the question of the extent of reduced severity with Omicron and the biological reasons for it, there’s the question of what this reduction might portend for the course of the pandemic. For nearly the entire duration of the pandemic, some experts have hypothesized that the coronavirus would eventually mutate to cause less severe disease. As the argument goes, it’s disadvantageous for a virus to kill its host before it can spread, and proponents of this idea often cite the virus that caused the 1918 Spanish flu, which still circulates in a far less deadly form every year.

But the idea of a tradeoff between severity and transmissibility, which experts say could explain Omicron’s evolution, is based on logic rather than data and is not guaranteed, Bhattacharyya says in his email.

“In my opinion, it’s pretty clear (despite conventional wisdom in some circles) that severity in COVID-19 happens late enough, and variably enough . . . that severity is unlikely to be significantly selected upon either way for SARS-CoV-2,” Bhattacharyya says. He offers up HIV as evidence that exceptionally lethal viruses can still spread just fine providing that their worst symptoms emerge after a delay—after they have time to spread to others. That, he adds, “illustrates the point that if transmission and severity happen at different times, what is selected upon is transmission. So then any link between transmissibility (including immune evasion) and severity would, in my opinion anyway, be circumstantial. . . . I don’t think there’s any inevitable relationship there, and I don’t think we’ve seen a consistent trend in either direction.”

Citing several papers on different variants, he adds that “prior to Omicron, more transmissible strains appeared to also increase severity.” Hyde agrees. “Delta showed us clearly that the virus could acquire mutations that both enhanced transmissibility and severity, so there’s no reason to think you can only have one or the other,” she tells The Scientist in her email. Moreover, she adds, “Omicron may well further evolve in the direction of increased virulence. With Delta and Omicron circulating together, there’s always the possibility of recombination.”

See “Plenty of Evidence for Recombination in SARS-CoV-2

That said, Chanda disagrees with Hyde. He tells The Scientist that with vaccines—especially future vaccines that specifically target Omicron—and therapeutics that slow transmission and mitigate symptoms would make it difficult for future coronavirus variants to mutate in such a way that they both spread more rapidly and cause more severe disease. That’s because these interventions would snuff out most infections with the virus before it could replicate and continue to mutate. Therefore, Chanda says, existing and upcoming interventions mean that SARS-CoV-2 is “being cornered into a mutational landscape” that will make it harder for more-dangerous variants to take hold. So even if there isn’t an explicit tradeoff between severity and transmissibility, he feels that there are decent odds that future variants won’t worsen in both regards.

Bhattacharyya notes that Omicron did not evolve from Delta, and argues that comparing the two is unlikely to reveal an overall trajectory in the evolution of new variants.

And whether or not a trend emerges toward decreased virulence, experts tell The Scientist it’s possible that the next SARS-CoV-2 variant to emerge may well be more severe.