A Blog by Jonathan Low


Dec 3, 2021

How Science Will Solve the Covid Omicron Variant

It's complicated but eminently doable. The issue is time: not that a couple of weeks - which is what it will take to determine to what degree current vaccines continue to provide protection - is long, but in this 24-7 news cycle world, exponentially exacerbated by social media - anything beyond immediate is considered interminable. JL 

Adam Rogers and colleagues report in Wired:

To gain a real-world picture of how much risk omicron poses, it will be critical to match any sequences to clinical data: who got sick, how sick they got, their demographics, and whether they'd ever been infected or vaccinated before omicron got to them. The next answers will build on existing work. That's those who've had COVID and recovered, or been vaccinated, or who've been treated with monoclonal antibodies. Then they check for "binding affinity," basically how much of an immune response those different sera mount against the protein, and that tells you how good the immune system is at beating the changes in the spike.

Starting last Friday, the race was on—between a virus and information about it. And for a while, the information moved faster, even though there was hardly any of it.

Scientists in South Africa identified a new variant of the virus that causes COVID-19—within days the World Health Organization gave it the spy-sci-fi name omicron—and because of the abundant smorgasbord of mutations in its spike protein, the nanomechanical tentacle that attaches and cracks into cells, science alarms started going off.

But to be clear, they were the "We should check this out" alarms, not the "Everybody lose their effing minds" alarms. Apparently they sound alike, though. Panic took flight as scientists identified omicron in 18 countries, triggering travel bans, border closures, stock market crashes, and, in the United States, holiday weekend worries that the world was headed back to March of 2020. Researchers in South Africa and Botswana have found the most cases thus far, though that may be an artifact of looking for them; on Tuesday, Dutch authorities announced that the earliest case they can identify is 11 days old, predating omicron's identification in South Africa.

That means the omicron variant is widespread and mysterious—a palimpsest wrapped in a hologram draped in a Rorschach test—because nobody knows nothin' yet. Public health authorities can't yet say whether it is more virulent or more transmissible than delta, which since last summer has crowded out most other variants of SARS-CoV-2. So panic; or don't. That's on you. Because now scientists have to work the problem.

The things scientists don't know, but need to: how efficiently does omicron move from person to person? Can it evade the immunity conferred by prior infection, or by vaccines? Does it cause more serious illness? "We need multiple types of data," says Angela Rasmussen, a coronavirologist at the Vaccine and Infectious Disease Organization-International Vaccine Centre in Saskatchewan, Canada. That means getting genomic and epidemiological data, understanding the variant's immunological differences, and collecting stats on breakthrough infections and hospitalizations.


That's all going to be complicated, because a crucial piece of information is missing: How long omicron has been spreading around the world. That new Dutch data suggests it has been longer than health planners first hoped. Whether this is the beginning of a wave—or the middle or end of one that no one noticed—is key. "It appears to have been caught at the beginning of an upswing, at a time where everybody has been focused on delta," says John Connor, a microbiologist at Boston University and investigator at its National Emerging Infectious Diseases Laboratories. "The nice part about having that information early is that the rest of the world can start examining all the questions that are raised by a new variant: Do our diagnostics still work? Does it look like the immune response generated by vaccines can still neutralize this virus?"

If this is just the beginning, let's say, then everyone with omicron might still be one tight-knit group, demographically or biologically speaking. That might make the variant seem more dangerous—faster-moving or making people sicker—if that group was for some reason more vulnerable than the general population. Or the opposite might be true. To figure that out, disease dynamics researchers might do "forensic accounting" to see how prior waves like delta behaved, and compare that to what's happening with omicron. That might say something about whether they're under- or overestimated how bad an omicron wave could be. "If I were to have assessed delta using only the time period that corresponds to about now, how wrong would I have been?" says Matthew Ferrari, director of the Center for Infectious Disease Dynamics at Penn State University.

In short: based on early data, scientists knew very little about delta. Now they know it inside out. They'll need the same patience to understand omicron. As a first step, more details of the variant's genetic structure, initially generated by scientists in South Africa, might help with early ideas about the variant's behavior as it spreads. "One can then infer from the genetics as to how this virus may escape antibody neutralization, whether it will escape vaccines or not," says Deenan Pillay, a virologist at University College London. But that's all inference, he adds: "One can never know, but one can make a calculated assessment based on what we know about the genetics of other variants."

The next answers will build on existing work—in fact, on the work that makes people so worried about omicron. Scientists have already taken modified versions of the spike protein and stuck it onto a virus that doesn't hurt people (usually something like Vesicular Stomatitis Virus, or VSV, denuded into a "pseudovirus"), then combined it with sera—basically the immunological parts of blood—from different kinds of people. Typically, that's those who've had COVID and recovered, or been vaccinated, or who've been treated with monoclonal antibodies. Then they check for "binding affinity," basically how much of an immune response those different sera mount against the protein, and that tells you how good the immune system is at beating the changes in the spike. "You find the titer or dilution that reduces the number of plaques that the virus or pseudovirus makes on the cells by 50 percent," says A. Marm Kilpatrick, an infectious disease researcher at UC Santa Cruz. "Usually one compares neutralizing titers of a new variant to a previous variant."

Researchers have these numbers for other COVID variants, including delta, alpha, and even the original one found in Wuhan. "What's especially interesting about omicron is that there are so many changes relative to what we've seen in the wild type and delta, the primary variants we've had so far," Ferrari says. "It's so many differences that we now have to worry about how those differences interact with each other."

The next step will be to do those same assays, virus versus immunity, with omicron itself. "That's taking the real virus," Ferrari says. "We can do them relatively quickly, but they have to be done in specialized settings—biosafety level 3." That means laboratories set up for dangerous respiratory pathogens, with air locks and everyone wearing protective equipment and respirators. Ferrari says those results are anywhere from one to two weeks away; Kilpatrick says they might come even sooner.

A problem, of course, is that this is still just bench-based information. "What we see in a lab is much simpler than what happens in real life; our real immune systems are obviously much more complex," says Emma Hodcroft, an evolutionary geneticist at the University of Bern. "And so that means that we cannot perfectly predict, just from looking at the sequences, how much immune evasion this variant might have, or how much more transmissible it is. We really need to wait for more data to see that."

To gain a real-world picture of how much risk omicron poses, it will be critical to match any sequences to clinical data: who got sick, how sick they got, their demographics, and whether they'd ever been infected or vaccinated before omicron got to them. "It's really important to note that we don't necessarily really have any indication from the sequence about whether the variant is more or less clinically dangerous," Hodcroft says. "It's also really important that the first people with this with omicron were not identified with this very long ago. And oftentimes, the more severe outcomes, we don't see them for a few weeks."

One thing that is clear, though, is that it's a mistake to blame South Africa for the variant's emergence. Researchers there are just very good at spotting variants and were transparent enough to warn the world. Still, omicron's numbers there may provide important clues to its clinical course. South Africa is a youthful country; 37 percent of its population is under 20 years old. (In the US, for comparison, 22 percent of the population is younger than 19.) Because younger people tend to fight COVID better, that may have skewed initial impressions that omicron causes mild illness. "One of the key things we need to do is really keep an eye on what's going on with the spread of the variant in other populations, particularly looking at how much infection there is in South Africa and what that means for hospitalizations," says Lawrence Young, a virologist at the University of Warwick Medical School. "If we're going to see any results around the ability of omicron to cause more severe disease or otherwise, it will be in South Africa."

A further confounder is that HIV-AIDS remains widespread across sub-Saharan Africa, where many infected people haven't had access to antiretroviral medications available in the Global North. That could mean disease synergy: someone whose immune system has been undermined by that disease could have been the incubator for the variant to develop its mutations—as happened last year with an immunocompromised patient in the United Kingdom. "In somebody with a strong immune system, the virus will only be able to evolve so much before that person's immune system sort of squashes the replication. But we know in immunocompromised individuals, the virus just runs amok," says Anna Bershteyn, an assistant professor and co-lead of the COVID modeling team at NYU Grossman School of Medicine. "There's a little bit of comfort there, because the evolutionary pressure of a virus running amok inside one body of an immunocompromised person is not necessarily going to push it evolutionarily into something that makes it really horrible for humanity at large."

Finding out what omicron does in humans, rather than petri dishes, will take a long time. Even the seemingly basic question of whether omicron causes more severe infections won't be easy to figure out. Researchers will use hospital data, so they have to wait until enough people actually get sick enough to need a doctor. Ideally, the people they study will all be unvaccinated, with no previous infection. "I'm not sure there are enough people left in South Africa that weren't exposed before for this data to be possible there," Kilpatrick says. If it isn't, he says, the alternative would be to study how effective the vaccine is at keeping people from illness so severe they have to be hospitalized.

Researchers will also try to compare the rate at which vaccinated people get breakthrough infections versus the infection rate among the unvaccinated—though the statistics get tricky. These would be observational studies, and they risk the potential of bias in which groups they include and how they measure them. For example, the difference between the two groups could be a function of which populations have access to hospitals and medical care. Kilpatrick says these studies could take four to six weeks.

Meanwhile, the proxy for virology is epidemiology. You have to measure how much omicron is out there relative to other variants. Researchers around the world will test new cases of COVID to see which variant people have, and whether omicron's numbers are growing faster than, say, delta's—to figure out if the new variant transmits from person to person more easily, or if it slides past people's immune systems better. "If we see fast replacement, that's indicative of either fast transmission, or it could be indicative of immune evasion," Ferrari says. "The two things are confounded right now. If we see a replacement of delta by omicron, we won't necessarily know immediately if that's because of increased transmissibility or decreased immune protection."

And after that—or amid all that—the boots-on-the-ground epidemiology of household transmission tracking will also start. That'll help give a better estimate of transmissibility, of whether omicron actually spreads faster and more aggressively than other variants. "Secondary attack rate, the number of people you spread the virus to, is a much more explicit measure of transmissibility, but it's a longer, slower process," Ferrari says.

While some researchers are figuring out what they need to know next, others are hoping to unwind the unhelpful things that have already happened. If sub-Saharan Africa wasn't actually the home of the variant—or even if it was, but the variant has long escaped—there's no scientific rationale for interdictions against travel. The bans "make no sense and send the wrong message. They should be reversed immediately," says Madhukar Pai, a physician, epidemiologist, and associate director of McGill University's International TB Centre. "Vaccine mandates and pre/post departure rapid testing can be used to protect travelers and borders."

Meanwhile, travel interdictions are preventing research from moving forward. For one thing, they're keeping people from getting isolated samples of the omicron variant. "The speed at which we get laboratory data is going to depend on how quickly we get access to virus isolates," Rasmussen says. "The travel bans have made it more challenging to get materials to and from southern Africa, so they are actively hindering research efforts."

In this view, reversing the bans would be the first step to ameliorating the North-South inequity that probably helped omicron emerge by throttling the availability of vaccines in the Global South. "I would love to see a powerful, concerted, global push for vaccinating the world," Pai says. Richer, whiter countries would have to stop hoarding vaccines, increase donations to the international vaccine-providing organization Covax, and pressure pharmaceutical companies to waive patent rights and transfer their technology to generic drug makers to increase production.

Until all that happens: panic, right?

No—because no matter what all the mutations Frankenstein-stitched into the omicron spike protein add up to, masks still work, especially the higher-grade N95s or KN95s. The virus is still much less likely to transmit in well-ventilated indoor spaces or outdoors. Vaccinations almost certainly still convey some protection against the variant, and booster shots keep that protection from waning over time. All the interventions that worked last week still work this week and will keep working for the "two weeks" that US National Institute of Allergy and Infectious Disease head Anthony Fauci said it would take to get better data. "Regardless of how little we know about omicron," says Beth Linas, a research epidemiologist at the independent R&D institute RTI International, "we know the best way to protect yourself and others now is to get vaccinated and boosted."

That's good advice, even putting omicron aside. Its arrival doesn't mean delta has departed. Around the world, that wave is still propagating. Austria is currently under a nationwide lockdown. The Netherlands is effectively closed from 5 pm to 5 am. Half-a-million people around the world get sick every week, and about 7,000 die. "Omicron is a spark that should not distract us from the fact that we're already in a burning building," Hodcroft says. People are still getting sick and dying from the old variant. There is still work to be done.


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