ABOVE: An artist’s 3D rendering of the Omicron variant of SARS-CoV-2 © ISTOCK.COM, CIPHOTOS

Newly shared preliminary data suggests that the Omicron variant of SARS-CoV-2 may target and infect tissues within the respiratory tract at different rates than do the Delta variant and other predecessors. In fact, some experts say, the Omicron variant may owe its enhanced transmissibility to its facility for infecting bronchial tissue far more than the lungs.

Findings from the research, which hasn’t yet undergone peer review, were shared online in a University of Hong Kong news release on Wednesday (December 15). In lung tissue taken from a human patient, the researchers found that the Omicron variant replicated roughly 70 times more in the bronchial tissue that makes up tubes leading into the lungs than did the Delta variant after 24 hours. However, Omicron variant replicated more than 10 times slower in lung tissue than the original coronavirus variant. It’s difficult to extrapolate clinical outcomes from this type of lab-based research, but the researchers suggest in the news release that the fast bronchial replication could explain why the Omicron variant seems to be so highly infectious—spreading more than twice as quickly as Delta, according to a not-yet-peer reviewed analysis reported in The New York Times. Other variants’ greater presence deeper in the lungs could explain preliminary reports suggesting that Omicron cases tend to be more mild than those caused by other variants—although there are conflicting analyses on that point, and well as alternative explanations.

The finding “was not surprising to me, based on the preliminary data that’s discussed in these circles,” says University of Minnesota pediatrician and infectious disease expert Beth Thielen. “The rapidity with which Omicron has outcompeted Delta in South Africa—that suggests to me that it has a fitness advantage.”

In order to measure infection rates, the researchers exposed samples of each type of human tissue to the Omicron, Delta, and original variants of SARS-CoV-2 and measured how well each infiltrated and replicated among the human cells after 24 and 48 hours. As of this article’s publication, the study authors haven’t responded to The Scientist’s request for comment.

The notion that an infection in the upper respiratory tract would lead to greater disease transmissibility makes sense, says Thielen. As people cough and sneeze, she says, the aerosols they expel would be chock full of Omicron—more so than if the infection were predominately lower in their lungs.

A virus that sits in the higher respiratory tract being linked to increased transmissibility but less severe disease also mirrors what scientists know about various strains of the flu, though Thielen warns that comparing the flu to SARS-CoV-2 is an imperfect extrapolation.

“If we think back to Influenza A H5N1 (‘bird flu’),”—which made headlines in the mid-2000s—“we tend to view it is highly pathogenic, but not particularly transmissible,” writes University of New England microbiologist and infectious disease expert Meghan May in an email to The Scientist. “This has been attributed to its preference to replicate in lower lung tissue and inability to replicate in the upper respiratory tract—the lung is ravaged, leading to severe disease, but few viruses are exhaled/inhaled by others.”

See “Omicron Appears to Evade Vaccines Better Than Other Variants

It also tracks that a virus that has less of an impact on the lungs might lead to less severe disease, says North Shore University Hospital pulmonologist Hugh Cassiere.

“Looking at this data and hearing the South African experience makes me think this data is probably going to hold up,” Cassiere says. Specifically, the preprint’s finding that there was one-tenth the level of lung infection with Omicron versus the original SARS-CoV-2 “is jiving with the data out of South Africa, where the hospitalizations aren’t as much on the rise as infections, or as they were with Delta, and neither is the death rate,” he says.

However, while the study found a difference in lung infection rates between the original SARS-CoV-2 and Omicron, May points that there was no statistically significant difference between Omicron and Delta replication rates in lung tissue after either 24 or 48 hours. “This tells me that the viral replication rate in lung tissue can’t be the entire story” behind any change in severity, she says.

One limitation of the study is that samples of lung and bronchus tissue are imperfect models for what would happen in an in vivo encounter with the virus. Neither model accounts for the immune response, which could protect against the virus, trigger a dangerous cytokine storm, or both, and they also don’t account for the role of vaccines. Thielen says that the work is still informative; there are simply additional factors that need to be taken into account.

“The research technique using discarded lung tissue seems like a reasonable ex vivo model to analyze viral replication,” University of Colorado Anschutz School of Medicine immunologist Aimee Bernard tells The Scientist over email. But she adds that questions not addressed in the university’s announcement, including the sample size and number of times the study was repeated, keep her from putting too much stock in the study’s findings. “If the number [of experiments] is 100, it could be meaningful. If the number is 1 or 2, it could be misleading.”

Alternative explanations

While data released this week by South African health insurer Discovery Health pointed to a lower rate of hospitalization in the country’s current Omicron wave than in previous surges, they may not present the full picture, as the Omicron variant has spread among a more heavily-vaccinated population than the original SARS-CoV-2 variant and Delta. Those and other context-dependent factors will make it difficult to get a clear picture of how Omicron itself compares to other variants.

“The tricky thing is that the vaccines are a real potential confusing factor,” Thielen says, adding that “we know vaccines prevent against severe illness and death.”

One way to validate the University of Hong Kong researchers’ hypotheses about clinical outcomes, Cassiere says, would be to analyze inflammatory biomarkers in the blood samples of coronavirus patients. Cassiere expects there would be fewer among those with the Omicron variant, suggesting a weaker inflammatory immune response.

See “When the Immune Response Makes COVID-19 Worse

Even if Omicron cases do tend to be relatively mild, the variant’s increased transmissibility makes it very dangerous. As lead study author and University of Hong Kong public health researcher Michael Chan Chi-wai says in the news release, “by infecting many more people, a very infectious virus may cause more severe disease and death even though the virus itself may be less pathogenic,” meaning that “the overall threat from Omicron variant is likely to be very significant.”

A more effective spike protein?

Another preprint shared by researchers from Harvard University and Massachusetts General Hospital on Tuesday (December 14) found that Omicron’s heavily mutated spike protein is better at infiltrating and infecting human embryonic kidney cells than those of past variants.

Immunologist and preprint coauthor Wilfredo Garcia-Beltran tells NPR that “it will probably pan out” that Omicron can infect people at a lower dose than other variants, “given that we’re looking at a variant with more efficient entry into human cells.”

However, the Hong Kong team’s findings could indicate that the Omicron variant is simply outcompeting the immune system through sheer numbers, Cassiere speculates, replicating to such an extent that the immune system can’t control it.

“If you have your castle surrounded, you could maybe fight off 10,000 soldiers—but not 100,000 soldiers or 1 million,” he says. “It wasn’t built for that.”