At most every turn, the coronavirus has surprised scientists.
The emergence of the omicron variant this fall, with an origin story that experts say remains shrouded in mystery, became the latest sharp turn for researchers trying to catch up with the virus and its variants.
Omicron, which has about 50 genetic mutations, developed outside of researchers’ view, with an evolutionary history far removed from the family tree of the once-dominant delta. Instead, its roots are in an old version of the virus thought to have faded away months ago.
“So many people thought the next big variant would be a sublineage of delta and suddenly we have omicron, which has all these mutations and then it took off,” said Pavitra Roychoudhury, a computational biologist at UW Medicine, a university-affiliated hospital system in Seattle. “The next question is: Where does it go from here?”
Scientists say they can outline scenarios for how the virus could evolve, but variants remain Covid’s unknowable wild card. In two years, they have rewritten the script so radically, many researchers are cautious to venture educated guesses of how Covid-19 will play out.
“There are various scenarios and they vary between rosy and gloomy,” said John Moore, a virologist and professor at Weill Cornell Medicine in New York. He emphasized, colorfully, that anyone saying they knew for sure what would happen next was full of it.
Omicron has only reinforced the folly of foretelling.
“I have just been so humbled and surprised by these variants of concern and the number of unanswered questions we have about them, where they came from, why they arise,” said Dr. Joshua Schiffer, a virologist and mathematical modeler at the Fred Hutchinson Cancer Research Center in Seattle.
When someone catches Covid-19, viruses infect their cells, and begin to replicate. Mistakes can happen during replication. Errors — or mutations — create variants, including ones that can cause the virus to act differently.
When multiple variants circulate within a population, they compete.
“What spreads is the fittest virus,” Moore said. Changes that make viruses more contagious or able to evade the immune system, including protection because of vaccination, give new variants a competitive edge.
The fast-spreading delta variant bullied its way across the U.S. last summer, boxing out other genetic versions of the virus that causes Covid-19 as it rose to dominance. For a time, it appeared to be the variant that would be our longtime foe. Some research suggested it caused more severe disease than the initial strain of Covid.
Then came omicron. Centers for Disease Control and Prevention modeling last week estimated omicron — more transmissible but less severe — has not only knocked delta from its perch but grown to represent 99.9 percent of cases in the U.S. Cases nationwide this month crested at all-time highs.
Considering that data, it’s tempting to proclaim delta finished, but scientists say it’s too soon to say for sure.
“It’s difficult to project whether one of the viruses will permanently displace another or whether they’ll coexist in the population or whether a new variant will displace both of them,” Schiffer said. “Unfortunately, I don’t think it’s possible to really know yet.”
The virus can change, but so does the immune landscape around it. Computation biologist and viral evolution expert Trevor Bedford said he expects roughly 40 percent of Americans to have been infected with omicron by mid-February, assuming, as the CDC does, that roughly one of every four cases is not recorded in national data.
As omicron infections accumulate, so will immunity in the population.
“About a month from now, we’re going to have a situation where a huge proportion of the population has exposure to omicron. There will be a lot of omicron immunity in the background,” Schiffer said, adding that in comparison to delta “it’s still not clear to me which is more contagious absent of immunity.”
He suspects whatever variant comes next will likely evolve to dodge previous immunity from omicron and other variants that people have been exposed to already.
As the proportion of omicron cases rises across the world, the chances of a delta resurgence could fall.
“I would be surprised if it was a sublineage of delta at this point,” Roychoudhury said. “The closer omicron gets to 100 percent, the lower and lower the probability.”
Many scenarios remain possible with omicron.
It’s possible omicron — through widespread infections and subsequent immunity — could push the virus into a more predictable pattern.
“Suppose omicron is the final, highly transmissible variant and we don’t have another one. That, obviously, is a very good outcome. That might not be the case,” Moore said.
On the other hand, omicron could also evolve to become more pathogenic or acquire the ability to better replicate in the lungs, Moore said, outlining several in a slew of possibilities.
Scientists have identified several sublineages of omicron, including BA.1, which accounts for most U.S. cases, and BA.2. Some countries, including Denmark, have observed a recent rise in the proportion of BA.2 cases, but it’s not yet clear what effect genetic differences between the subvariants mean for disease severity, transmissibility or immunity.
“Whenever you see one variant outcompeting another, it tells you, potentially this could be more transmissible or immune evasive,” Roychoudhury said. “Are there any specific mutations that could help this branch of the omicron subtree take off?”
Omicron’s mysterious origin story illustrates why scientists are reluctant to make predictions. Researchers still don’t know where the variant came from.
When the variant emerged last fall, its closest evolutionary connection documented in the databases that track such things was from mid-2020, according to a tweet from Bedford.
Somehow, omicron accumulated mutations outside of scientists’ view, which is primarily provided by genomic sequencing, a technology that allows researchers to track changes to the viruses’ genome.
Scientists have three main theories of how omicron developed so stealthily.
In the first, the virus infected an immunocompromised person unable to fight the virus. The virus, which would normally be neutralized in a handful of days, instead replicated over weeks or months. It accumulated dozens of key mutations before spreading to new hosts.
The second possibility is that the virus spread quietly in a population of people who were not having samples tested or sequenced by researchers, all the while accumulating mutations as it spread from person to person.
In the third, the virus transmitted from a person to an unknown animal species, mutated and then spilled back into humans with new characteristics.
“If the immunocompromised host story is true, and it’s what I find most plausible, then the variants are coming from a single person and it’s a random, stochastic introduction into the population,” Schiffer said. “You could imagine a situation where somebody has an infection with delta right now and had that infection for three months and the virus is mutating in their body.”
It’s a dynamic that could make predicting future variants challenging. Global vaccination efforts and widespread genomic sequencing will be key to limiting the risk of future variants and having the resources to detect them early.