Inside the race to test omicron's true threat
Microbiologist Pei-Yong Shi has studied all the variants: alpha, beta, gamma, delta, "delta-plus," lambda and mu. So he was ready for omicron, the variant that incited global anxiety unlike any of the variants that came before.
Like most scientists, he was shocked by the sheer number of mutations. He also knew exactly what to do next.
Shi runs a high-containment laboratory at the University of Texas Medical Branch, in Galveston, and collaborates closely with Pfizer. Over Thanksgiving, his team began engineering a replica of the new variant to test against the antibodies generated by vaccines. But it doesn't happen overnight: It will take about two weeks to build the omicron replica, another few days to confirm that it's an accurate facsimile, and one more week to pit the virus against blood samples from vaccinated people.
Shi and colleagues around the world are in an urgent race to gauge the danger posed by omicron, which is rapidly seeding itself everywhere. As the tally of cases mounts, what happens inside labs over the next few weeks will help scientists determine the true potential of the virus, tipping off government officials and pharmaceutical companies about whether they need to revise their global vaccination campaign.
His message: Be patient. Wait for the data.
"I think there is a lot of overreaction, and we just have to sit tight," Shi said. "There are no results yet, these are just the mutations. What does that mean? We have to see."
There's no doubt that omicron is different - and worrisome. It is riddled with mutations, some known to help the coronavirus dodge the body's immune defenses. Others are newcomers, a complete mystery. Omicron has more than 30 genetic changes in the coronavirus spike where vaccines train their firepower.
But the scientific community is focused, not freaked out - perhaps because it has seen this movie before: A new variant pops up, and everyone on the planet is desperate to know how bad it is. Science ensues.
First, researchers will test how well the virus is equipped to dodge current vaccines. At the same time, they will watch closely what happens in the real world. Most scientists are betting omicron will have some capacity to slip past the virus-blocking antibodies that form a primary line of defense - but no one knows yet how deft an escape artist it will turn out to be. Many also believe vaccines are likely to retain a level of protection, particularly against severe illness.
Even the worst-case omicron possibility - faster-than-delta transmission, a sharp erosion in the protection afforded by vaccines and higher rates of severe disease - isn't a hopeless scenario. Companies will reboot omicron-specific vaccines and test them. Vaccine-makers have already begun adapting their vaccines as a precaution, and even ran a dress rehearsal of this strategy earlier this year, against the beta variant.
Omicron is still studded with question marks. Does it, as some preliminary data from South Africa suggest, spread more easily than delta? Can it evade the multiple lines of defense mustered by vaccines? Is it more pathogenic - capable of causing severe disease?
"Working on it! No data yet!" Penny Moore, the scientist whose laboratory in South Africa first revealed the immune-evading potential of the beta variant, wrote in an email. "We have to create the spike by introducing the many mutations, or grow the live virus."
Matthew B. Frieman, a coronavirus expert at the University of Maryland School of Medicine, hopes samples of the virus will arrive in the next week so he can start experiments in lab dishes and vaccinated mice. Many people, including him, had shared the hope that as vaccine eligibility was expanded to younger children, it might be a last steppingstone before resuming more normal life.
Instead, his Thanksgiving was interrupted by phone calls and Zoom meetings, continuing a relentless pace of work with few slow periods since January 2020.
"There is an urgency to know, but it's been urgent for two years," Frieman said. "The good thing is, we know what to do. We've been planning for this, and we know the science to do. We know what assays work and how to do them. We have mice vaccinated and ready to be infected."
Speculation that coronavirus vaccines could falter against omicron has sent tremors through financial markets and concern through a pandemic-weary public wondering whether Christmas is canceled or travel plans need to be rescheduled. Most experts are measured.
"We're in a position of gathering data," said John Mascola, director of the National Institutes of Health's Vaccine Research Center. "The virus has proved to us that it has an uncanny ability to evolve rapidly, and it has the ability to change in a way that dramatically changes the variant that is predominant in the world."
But will omicron usurp delta, just as delta took over from alpha?
"We need about two more weeks" to see laboratory data and what the virus does on the ground, Mascola said.
Scientists do know the path to answers. They've walked it many times during this pandemic.
If they decide a revised shot is necessary - far from certain at this point - the process will take about three months for the messenger RNA shots.
"This is essentially the same drill, as I call it, that we are always using. We stay very . . . levelheaded about it," said Kathrin U. Jansen, Pfizer's head of vaccine research and development. "What we are seeing right now is everyone is afraid of the unknown. . . . What I think, as a scientist, is that what's unknown, we don't address that with fear, but with studying that and getting the data."
The Texas scientists, clad head-to-toe in protective gear, work in secure biosafety laboratories. They start with the original strain of coronavirus, the virus isolated in Snohomish County, Wash., nearly two years ago. They synthesize the omicron spike gene, with its dozens of mutations. Using the original virus as a scaffold, they swap in the new spike - steps they've done for alpha, beta, gamma, delta - and now omicron.
Once the virus is ready, the Texas researchers will test it against a panel of 20 antibody-rich blood samples taken from people fully vaccinated with the Pfizer-BioNTech coronavirus vaccine. This will tell them how good the virus is at evading this key line of immune defense and allow them to compare it to other variants.
Other labs are working on similar experiments with blood from vaccinated patients, including those who have received booster shots.
Mehul Suthar, an immunologist at Emory University, is eager to study omicron itself in his high-containment laboratory, where he typically dilutes a vaccinated patient's blood in stages to see at what point a variant is able to break through the antibodies and infect cells.
"We're all scrambling to get ahold of the virus," Suthar said.
Other laboratories don't experiment with the virus itself, but instead create pseudoviruses - a version that superficially looks like the variant, and is capable of infecting an individual cell in lab experiments, but that is designed to be incapable of replicating. These pseudoviruses carry the spike protein of the variant but are easier to work with because they don't require layers of protective gear and biocontainment laboratories.
Collectively, those tests will show how much antibody protection drops against omicron. If it's a big enough reduction, vaccine-makers may decide to reboot their shots with new genetic sequences that match the changes in omicron's spikes. They're already laying the groundwork.
But that is only one line of evidence. Omicron's true threat will be revealed not only by what it does in a laboratory dish, but also by what it does outside the lab.
A preprint study from South African scientists, for example, found evidence that people previously infected with the coronavirus may not have much of a shield against omicron, with reinfections three times likelier than during previous outbreaks. The paper did not shed light on how severe reinfections were or whether vaccinated people were more likely to experience breakthrough infections when exposed to omicron compared with their response to other variants.
"It's going to be a deluge of unfiltered information - press releases, preprint servers, some people making opinions, but I think the scientific community has definitely engaged very quickly, so hopefully a scientific consensus will emerge," said Dan H. Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston.
"To some extent, it's: Here we go again, we have another job to do," said Barouch, who helped develop the Johnson & Johnson vaccine.
Scientists debate how well omicron's ensemble of mutations will help it get around immune defenses. But most agree that even if it barrels through that key line of defense, it won't zero out the protection from vaccines.
"We are no longer a blank slate. We have preexisting immunity, even though it may not be perfectly matched," said Barney Graham, a key architect of the coronavirus vaccines, who recently retired from the National Institutes of Health.
Previous variants already taught that lesson. The beta variant posed a clear threat to immune protection in a dish. But clinical trials of the Johnson & Johnson and Pfizer-BioNTech vaccines showed they still offered protection to people.
Although it is difficult to predict from a virus's mutations how it will act, many scientists say they think omicron may ultimately require a revised vaccine.
"At this point, the wise thing to do is to start the early steps for making a booster against this variant," said Jesse Bloom, an expert on viral evolution at the Fred Hutchinson Cancer Research Center in Seattle.
The major vaccine companies are at work doing that, just in case. Pfizer and BioNTech have announced that adapting their vaccine will take six weeks and that the first batches could be shipped within 100 days. Moderna is formulating an omicron-specific candidate, a process that typically takes 60 to 90 days based on its experience doing so against beta and delta. Johnson & Johnson is pursuing an omicron-specific shot.
Instead of running time-consuming large-scale trials that depend on waiting for people to get ill, vaccine-makers expect to be able to show that their revamped vaccines are safe and effective by measuring immune responses in blood samples taken from study participants.
"We can turn the key relatively quickly and start to produce the updated vaccine," Pfizer's Jansen said.
This could also be the moment for second-generation vaccines designed to be variant-proof by triggering a broader swath of immunity beyond antibodies.
"Our premise was that this would happen," said Andrew Allen, chief executive of Gritstone Bio, a company whose vaccine formula is designed to rouse protection from T cells, the immune-system warriors that kill infected cells. "It is naive to think that the very first vaccine we made in the very first hot minutes of the pandemic would be the very best vaccine we could make."
The idea behind Gritstone's vaccine is that a broader set of immune defenses will free the world from constantly trying to play catch-up to the latest mutant strain of the virus.
But unless more of the world becomes vaccinated, the frenzy of worry is likely to continue to repeat.
"If we don't develop systems to immunize the whole world in three months, instead of three years, we are not going to be successful against these kind of pandemic threats," Graham said. "Because viruses adapt and they change, and unless we develop generalized global immunity more readily, we will always be faced with chasing our tail."
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