As this year begins, the Omicron variant is smashing COVID-19 infection records across Europe, North America, Africa, and Australia. With massive numbers of people infected or in quarantine, tens of thousands of flights and trains have been canceled, and work and schools disrupted. Earlier in the pandemic, the frightful, near-vertical rise in cases would have triggered stringent lockdowns. Not this time: Many governments are banking on early indications that vaccines still protect against severe disease and that Omicron may be a gentler variant.
It’s a risky bet, because scientists still can’t predict Omicron’s ultimate toll. Initial data from South Africa, Denmark, and the United Kingdom suggest it causes less severe disease, but they come with major caveats. And even less severe cases can strain hospitals already at the edge of their capabilities. In a worrying sign, COVID-19 hospitalization rates in the United States surged this week.
Virologists, molecular biologists, and epidemiologists are biting their nails and hoping cases will soon peak and begin to fall. They are also working at top speed to sort out the properties of the new variant. Here are some of the key questions they are trying to answer.
How does Omicron differ from previous variants?
Just 6 weeks after its discovery, it’s clear the new strain behaves very differently from previous ones. Early studies by several groups hinted that Omicron replicates less well in lung cells than other variants, and two new studies have suggested a possible mechanism, based on how it enters human cells.
SARS-CoV-2 has two entry routes. After binding to ACE2, a receptor protein on the cell surface, virus particles can fuse with the cell directly when another human protein called TMPRSS2 cleaves the spike protein on the virus’ surface. Alternatively, after binding to ACE2, the virus can be swallowed by the cell in a vesicle called an endosome. The virus then escapes into the cell’s cytoplasm with the help of other spike-cleaving proteins called cathepsins.
Early lab studies showed TMPRSS2 cleaves Omicron’s spike protein less efficiently than that of other variants, hampering the first, direct route. And in a preprint posted last week, virologist Joe Grove of the University of Glasgow and others showed that blocking TMPRSS2 with the chemical camostat inhibited pseudoviruses carrying the spike of the Alpha or Delta variants in cell culture, but not those carrying Omicron’s. Conversely, blocking cathepsins with a compound named E64d inhibited viruses carrying Omicron’s spike, but not Alpha’s or Delta’s. Those data make “clear there’s a very, very strong preference now for the endosomal route,” Grove says. (Another new preprint, by virologist Thomas Peacock of Imperial College London and colleagues, had similar findings.)
Some researchers argue Omicron may spare the lungs and cause milder disease because TMPRSS2 is more common on cells in the lower airways, but there are few data to support that, Peacock says. Cells infected with Omicron may also be less likely to fuse with neighboring cells to form large cells called syncytia that might be a cause of severe disease.
“For now, the combined data seem to point in the direction of a less severe clinical picture, possibly explained by changes in how the viruses infect and which cell types they infect,” says virologist Marion Koopmans of Erasmus Medical Center.
Could these changes in viral biology explain why Omicron is spreading so fast?
Perhaps. It’s possible they have shortened the time between exposure and onset of symptoms, which studies suggest is only 3 days for Omicron, down from about 4 days for Delta and more than 5 for previous variants. This is likely contributing to the steep rise in COVID-19 case numbers. But other changes may play a role as well.
One is the variant’s ability to get around immunity provided by previous infections and vaccines. A study of SARS-CoV-2 spread in nearly 12,000 households in Denmark, posted as a preprint on 27 December 2021, provides some of the clearest evidence of Omicron’s advantage. Economist Frederik Plesner Lyngse of the University of Copenhagen and the Danish Statens Serum Institute and his colleagues found that in households with a Delta outbreak, the unvaccinated were twice as likely to be infected by a household member as those who were fully vaccinated. In households struck by Omicron, unvaccinated and fully vaccinated people had roughly equal chances of catching the virus.
That doesn’t mean COVID-19 shots don’t work; other data clearly show they still prevent severe disease. And in the Danish study, a booster shot cut the risk of infection by Omicron in half. Being vaccinated also reduces an infected person’s chance of infecting others, Lyngse notes: For both variants, an unvaccinated case was 41% more likely to infect another household member than a fully vaccinated one.
There’s another possible explanation for Omicron’s explosive spread that the household study would not be able to pick up, notes epidemiologist Bill Hanage of the Harvard T.H. Chan School of Public Health. If the virus is really better at replicating in the upper airways, it might be expelled more readily into the surrounding air, making it more likely to trigger superspreading events. And if it truly causes milder illness, even people who shed a lot of virus might have few symptoms, making them more likely to be out and about. If so, banning large gatherings and closing down nightlife and restaurants might be even more effective at slowing the spread of Omicron than that of previous variants, Hanage says.
Is Omicron sending fewer people to the hospital than previous variants?
Data from South Africa, where cases have already started to decline, suggest Omicron put one-third as many people in the hospital as the Delta variant did. But previous infections and the country’s relatively young population may have helped keep severe cases low.
Initial hospital data from England and Denmark also suggest Omicron cases are less severe. But those countries have high vaccination rates, and there, too, Omicron has spread most quickly among younger adults. Severe cases may increase in the wake of holiday parties where people of all ages mixed. “If we see that Omicron is capable of causing severe disease in older age groups … I think it could be much worse than most people are thinking about at the moment,” Hanage says. The U.S. picture looks less hopeful: More than 100,000 people there were hospitalized with COVID-19 when Science went to press—up from 75,000 a week earlier.
Moreover, there are signs Omicron can trigger dehydration from fever, vomiting, and diarrhea and can exacerbate other health issues such as diabetes. Such cases need less intensive care, but can still overwhelm hospitals. “I’m hearing story after story after story of hospitals that are full, health care workers that are infected, that can’t do their job,” says Maria van Kerkhove, an epidemiologist at the World Health Organization (WHO).
How severe Omicron is in people who are “immunologically naïve”—neither vaccinated nor previously infected—remains an open question. They are now a minority in most countries, but they too could add to the hospital burden if they get seriously ill. Deaths in Ghana, Ivory Coast, and Madagascar, where vaccination rates are low, are increasing sharply as COVID-19 cases surge.
Is Omicron the last variant of concern?
Probably not. More variants with Omicron’s ability to evade immunity and spread successfully are likely to emerge, says Aris Katzourakis, who studies virus evolution at the University of Oxford—and they may prove more virulent than Omicron. After all, even Omicron itself may not have evolved to cause less severe disease, Katzourakis notes. It may be milder than Alpha or Delta, but it branched off from the family tree before those variants emerged. “Is it milder than what it evolved from? I don’t think we know the answer to that,” Katzourakis says.
The next variant to make global headlines may already be circulating. WHO is tracking two “variants of interest” and three “variants under monitoring,” as well as 30 sublineages of Delta, Van Kerkhove says. “There are many more Greek letters that we can potentially go through.”
But Omicron itself may help tame whatever comes next. Vaccination and natural infections have exposed many millions of people to earlier versions of SARS-CoV’s spike protein, training their immune system to respond to those variants. Infections with Omicron, whose spike looks different, will likely both strengthen and broaden immunity, Hanage says, hopefully making new variants less dangerous. “I suspect that immunity, post-Omicron, will be pretty broad,” Hanage says. “But I don’t want to bet on it.”