Early lab studies hint Omicron may be milder. But most scientists reserve judgment | Science

The new SARS-CoV-2 variant exploding around the planet is forcing humanity to adapt at a breakneck speed. This week, countries across Northern Europe imposed stringent new measures to try to bring down soaring case numbers. On Saturday, The Netherlands issued a near-complete lockdown of public life and allowed residents to receive no more than two guests per day—with an exception for Christmas and New Year’s Eve, when four visitors are allowed. Denmark, which lifted all pandemic restrictions in September, closed theaters, concert halls, museums, and other public spaces on Friday and banned alcohol sales after 10 p.m.

Driving those decisions is alarm at Omicron’s wildfirelike spread—and caution in the face of major uncertainty. If Omicron makes people just as sick as the Delta variant, models predict a staggering rise of hospitalizations—many times what most health systems can handle. If Omicron causes milder disease than Delta, things would be less catastrophic—but even then, “a considerable overload of the hospitals is to be expected,” a group of experts warned in a 19 December report to the German government. A massive Omicron wave might also lead to many more cases of Long Covid.

It will take weeks before epidemiological data deliver a clear verdict about disease severity. But preliminary lab data, and a few real-world clues, are raising hope among optimists, while others reserve judgment. “If it turns out there is reduced severity from Omicron, there are now potentially some mechanisms that might help explain this,” says Tom Peacock, a virologist at Imperial College London (ICL). “On the other hand there may be some mechanisms that could explain the opposite. So it’s still a bit of a mess until the real-world data crystallizes.”

South Africa has seen only a modest increase in hospitalizations for severe COVID-19, even 1 month after cases started to explode there. “We’re all still really cautious about that data, but it seems to be holding out,” says virologist Wendy Burgers of the University of Cape Town. Moreover, early signs suggest South Africa’s Omicron wave may not last long. Cases are already decreasing in Gauteng province, the outbreak’s epicenter, which is a bit of a mystery given how transmissible Omicron seems to be, says Trevor Bedford, a bioinformatics specialist at the University of Washington, Seattle, and the Fred Hutchinson Cancer Research Center. He suspects part of the explanation is that more infections than usual went unnoticed because they were mild or asymptomatic, so the real peak was even larger than official statistics showed.

But early data from Europe, which has an older population than South Africa, are less hopeful. Based on early hospitalization data, for example, a report by modelers at ICL concluded there are “at most limited changes in severity compared with Delta.” “I don’t know how to square these two things, and that is probably giving me the most pause at the moment,” Bedford says.

Lab data offer a little more hope. Antibodies resulting from vaccination or infection have been shown to lose most of their power against Omicron, but another immune system defense—T cells, which recognize and kill infected cells in the body—appears to do better. Burgers and her colleague Catherine Riou tested the response of T cells from people who had received one or two doses of the Johnson & Johnson COVID-19 vaccine or two doses of Pfizer. In all three groups, the T cell response to Omicron dropped by a modest amount compared with the original strain of the virus—between 20% and 30%, the researchers estimate. That’s much less than the drop in antibody efficacy. “T cells are holding out against Omicron,” Burgers concludes. “And the data is very consistent across vaccines.”

That may help explain South Africa’s low hospital burden, Burgers says. “Of course it could be other things about the biology of this variant,” she adds, “but certainly from everything we know about T cells, this is what they do—control a virus once you’ve been infected. So this is their time to shine.”

Meanwhile, researchers studying Omicron’s behavior in the lab are turning up surprises. “There is something very weird about this virus,” Peacock says. Normally, SARS-CoV-2 replicates well in Vero cells—kidney cells from African green monkeys—genetically engineered to be studded with the virus’s receptors, ACE2 and TMPRSS2. With any previous strain, such infections lead to visible areas of damage in the cell culture called plaques. But that’s happening much less with Omicron, Peacock says. “It’s not liking the cell lines that have been our bread and butter all the way through.”

Researchers in Hong Kong have seen notable differences in another system, in which the virus infects healthy lung tissue taken from lung cancer patients during surgery. Omicron replicates much faster than previous variants in cells from the bronchi, but much slower in cells from lower in the lungs. “Whilst the other strains take off after about 72 hours in the bronchus, this one goes up within 24 hours,” says John Nicholls, a pathologist at the University of Hong Kong. The findings, published in a short note online and submitted to a journal, might explain why Omicron spreads better while perhaps causing less severe disease. Virus in the bronchi is more likely to be exhaled, whereas deep in the lung it is likely to cause more severe disease. But Nicholls urges caution in interpreting the data. “We’re being very, very careful,” he says.

Some of Omicron’s many mutations initially didn’t bode well. Scientists have zeroed in on changes close to the furin cleavage site, a motif in the spike protein that allows it to be more easily cleaved, which is an important step in the infection of a human cell. Mutations around this site appear to have made both Alpha and Delta more transmissible and better at infecting cells. Omicron carries the mutation Alpha had, P681H, and another one close by called N679K. “Just from sequence gazing, we thought, this is probably going to have Delta-like transmissibility and pathogenicity,” Peacock says.

But a preprint by virologist Ravi Gupta of the University of Cambridge suggests the opposite could be true: Using viruses modified to carry the spike protein of Omicron and other variants, they found that Omicron’s spike is cleaved much less efficiently than Alpha’s or Delta’s. That could explain why Omicron might be worse at infecting certain cells than previous variants.

His preprint also suggests another contrast. Research on previous variants has suggested SARS-CoV-2 can cause neighboring cells to merge into syncytia, large cells with multiple nuclei. Syncytia have been found in the lungs of patients who died of COVID-19 and may be related to disease severity, Gupta says. Kei Sato, a virologist at the University of Tokyo, has shown that the more pathogenic Delta variant was more likely to cause syncytia in cell culture. Now, Sato and Gupta both have data suggesting syncytia may be rarer with Omicron. Taking all of the data together, Gupta says, “I think the evidence is mounting … that the virus potentially causes less progression to severe disease.”

The role of syncytia is far from clear, however. SARS-CoV, the virus that causes severe acute respiratory syndrome, has not been shown to cause them. And although SARS-CoV-2 seems to trigger syncytia in cell culture, they don’t appear in animal models, Nicholls says: “In the hamsters we looked at, in the mice we looked at, you don’t get the syncytia.” Christian Drosten, a virologist at Charité University Hospital in Berlin, says syncytia in COVID-19 patients may have other explanations, such as the reactivation of herpes infections, which are known to cause syncytia formation.

Peacock says it’s simply too early to draw firm conclusions from the lab studies. “I think there’s definitely something interesting going on there. But I wouldn’t like to bet that other people are definitely going to find the exact same thing,” he says. Gary Whittaker, a virologist at Cornell University, says Omicron seems to behave more like seasonal coronaviruses, which are often hard to grow in cell culture. That makes experiments on the new variant even harder to interpret, he says. “We’ve got to get a system which is much better matched to the virus, otherwise we will very easily get led astray if we’re not careful.”

Getting firm answers from the lab may well take until Easter, Drosten says. By that time, the world may have learned how much severe disease the variant causes the hard way. “So far, variants that replicate more have caused more disease,” Drosten says. “So we would do well to be very careful with this variant.”