Whenever a fresh coronavirus variant emerges, the public often hungers for answers. What could it mean for my family? My job? My health?

Since the omicron variant was first reported, the common response from health experts — cited across CNN to The New York Times to NPR — is that it could take “two weeks” to know whether immunity and vaccine protection will remain effective against this new threat.

Why two weeks? A fortnight is a weirdly specific timeframe?

The main reason behind the wait is that a legion of virologists need this time to tease apart omicron's attack patterns. This new variant's large amount of mutations has made this work harder than it typically is. Omicron has about 50 mutations — twice as many mutations overall as delta.

Also contributing to the delay is the lag time between catching the virus and being hospitalized. It typically takes about seven to 12 days. Most of the early omicron cases were spotted in college students who developed mild disease, according to their doctors. But younger adults are way less likely to experience severe COVID, and wave after wave has taught us that these youths also tend to be on the leading edge of surges. So, these early cases do not offer much clarity on omicron’s severity.

“I was completely shocked and surprised to see the number of mutations,” said Dr. Ned Landau, a microbiology professor at New York University Grossman School of Medicine. “It took me a while to figure out that this was for real.”

Landau is leading one out of the hundreds of labs that is working with the World Health Organization to determine if omicron can bypass our immunity. After meeting with the WHO on Monday morning, Landau walked WNYC/Gothamist — step-by-step — through what goes into the process and why it will take about 14 days.

Two Ways To Build An Arsenal

A couple of paths exist. The first involves collecting the omicron variants from patients and growing the virus inside petri dishes in a lab.

“There are labs, particularly in South Africa and other places in the world that are isolating the virus. That will take a few days,” Landau said. “One would think that in about two weeks or so, there ought to be nice stocks available of the virus that will be shared worldwide with scientists.”

But working with the actual virus can obviously be risky, especially when all scientists really want is to answer a simple question about our vaccines.

Another approach involves making what’s known as a pseudovirus.

“These pseudoviruses are kind of like little virus particles that are completely harmless to the laboratory workers,” Landau said. But scientists can take pieces of a coronavirus variant and plug them into a pseudovirus shell to see how the former works.

In this case, they want to plug in the spike protein, the part that allows the coronavirus to pierce our cells. These spikes cover the virus like the head of a medieval weapon. And to no one’s surprise, our immune systems primarily try to block these spikes to prevent an infection.

A medieval bludgeon (or mace) is covered with spikes.

A medieval bludgeon (or mace) is covered with spikes.

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A medieval bludgeon (or mace) is covered with spikes.
StockPhotoAstur via Shutterstock
This illustration shows the structure of the SARS-CoV-2 virus, with its spike protein highlighted.

This illustration shows the structure of the SARS-CoV-2 virus, with its spike protein highlighted.

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This illustration shows the structure of the SARS-CoV-2 virus, with its spike protein highlighted.
National Institutes of Health via Twitter

To determine how omicron attacks in a laboratory, scientists must physically build an arsenal of these spikes and toss them at cells in a petri dish.

When new variants have come along in the past, building this arsenal has been fairly straightforward, Landau said. Scientists just took a previous version of the spike and made a handful of genetic changes. But omicron has about 30 of its 50 mutations in its spike, compared to a mere nine in the delta variant spike.

“But omicron has so many mutations that we cannot just use the simple, quick approach,” Landau said. “We have to kind of start from scratch and make the whole gene on a DNA synthesis machine.”

These 3-D renderings of coronavirus spike proteins show the list of mutations in the delta versus omicron variants.

These 3-D renderings of delta versus omicron spike proteins show the positions of mutations (red).

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These 3-D renderings of delta versus omicron spike proteins show the positions of mutations (red).
COVID-19 Genomics UK Consortium

This process on its own can take about a week. That’s partially because the gene responsible for making the spike has about 3,800 nucleotides — the basic rungs that make up its ladder-like genetic code. These rungs are also known as base pairs.

“It takes the machine maybe two or three days to make that DNA that long,” Landau said. “We then have to make sure that the machine made it exactly correct. Every single one of those base pairs has to be correct.”

It’s like being asked to copy 3,800 words from your favorite book by hand. You might make some typos. The same applies to a DNA synthesis machine.

What A Red Flag Will Look Like

Once a lab has a true copy of omicron’s spike gene, it can be inserted into the pseudovirus. Researchers then allow the pseudovirus to replicate for a few days until the arsenal is large enough to test the integrity of our immunity.

To do that, Landau’s team will grow human cell lines in a petri dish. The team typically uses cells that were extracted from one man’s lungs decades ago, given the coronavirus is a respiratory disease.

The researcher will also mix in antibodies, a core part of our immunity defenses. Those are typically collected from the blood of patients who’ve recovered from a coronavirus infection or people who are vaccinated.

“When they infect a cell, the cell lights up and we can measure the amount of light,” Landau said. “So we can use that virus to very quickly determine whether antibodies from people are able to block infection of that virus.”

They will run each experiment multiple times to make sure the results are consistent. While this laboratory process might seem a long way from a human body, multiple studies show that pseudovirus experiments can faithfully gauge how antibodies and vaccines will behave against coronavirus variants.

"So you add up three days here... and two days there... and three days there, and after a while, you get to about two weeks," Landau said.

For a couple of reasons, Landau and other researchers are cautiously hopeful that infection — the variant’s ability to enter our cells and embed in our organs — will be the main thing influenced by omicron’s mutations. They’re hoping immunity against severe disease will remain intact.

“The sheer number of mutations is not necessarily indicative of whether a virus is more transmissible or more virulent,” said Bruce Y. Lee, a public health policy expert at CUNY and executive director of Public Health Informatics, Computational, and Operations Research. “It all depends on where the mutations occur.”

Within the spike is a special region called the receptor binding domain (RBD). It is what allows the spike to stick against our cells.

Vaccinated people and those who’ve recovered from COVID-19 infections produced antibodies (Y-like shapes in red, green and blue) circulating in their blood that target different parts of the coronavirus spike protein (gray).

Vaccinated people and those who’ve recovered from COVID-19 infections produced antibodies (Y-like shapes in red, green and blue) circulating in their blood that target different parts of the coronavirus spike protein (gray).

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Vaccinated people and those who’ve recovered from COVID-19 infections produced antibodies (Y-like shapes in red, green and blue) circulating in their blood that target different parts of the coronavirus spike protein (gray).
University of Texas at Austin via NIH

After an infection or after taking a vaccine, our immune systems make antibodies that bind all over the spike. But the ones most effective at neutralizing the virus stick to the receptor binding domain. A bunch of omicron’s mutations are squarely in the RBD, suggesting the variant might have an advantage with bypassing our immunity and entering cells.

“Antibodies that bind outside the RBD would not block an attachment to cells,” Landau said. “But there are other things that antibodies do besides just interfering with the attachment of the virus to your cells, and so those other antibodies could still be helpful.”

And then there are T-cells, another component of the immune system. Those cells are essentially the bodies’ wardens, and they’re also able to recognize various regions of a spike.

Landau said the T-cells can hone in on several parts of the spike that aren’t mutated in omicron. But the T-cells are not so good at preventing a person from being infected in the first place. They are better equipped at suppressing the virus from replicating after you’re already caught the virus.

“It's possible that with this omicron virus, that the vaccines will still work quite well, but that it will be more of a T-cell dependent response,” Landau said.

The Takeaway

If that holds true, omicron would struggle to fill hospitals with patients in places where vaccination rates are high. Recovering from an infection can provide solid natural immunity, but it happens less frequently. Hence why vaccination is recommended for recovered patients. The World Health Organization has also stated this week that the omicron variant carries an increased risk of reinfection for recovered patients, but it hasn’t released the preliminary evidence behind this assessment.

Think of it as a poker game. So far, the COVID vaccines have allowed a person to draw a Full House almost every time, reducing the odds of severe disease by 90%. With natural immunity, the odds are worse. As WNYC/Gothamist reported in our holiday guide to judging COVID risk, Americans relying on natural immunity were five times as likely to experience a hospitalization relative to vaccinated people in a recent study.

The COVID-19 vaccine can also lose a bit of effectiveness and still thwart coronavirus transmission through a population, according to research published by Lee’s lab in summer 2020. Back then, before any highly transmissible variants had hit the mainstream, vaccine effectiveness could have been 70% against infection and still tamed the spread of new outbreaks.

You want the effectiveness to still be in the 70s, certainly the higher, the better.

Dr. Bruce Y. Lee, CUNY and PHICOR

“It's still preferable not to go below that range,” Lee said. “You want the effectiveness to still be in the 70s, certainly the higher, the better.”

The delta variant and waning immunity had already started pushing the effectiveness of the COVID vaccines below the 70 mark when it comes to blocking infection. The original two doses of Pfizer and Moderna as well as the single shot from Johnson & Johnson are holding steady against severe disease, but boosters are now needed to stymie the spread.

Time will tell if omicron worsens our defenses against infection. But the Centers for Disease Control and Prevention has strengthened its advice on booster shots this week. The additional doses are now recommended for all adults 18 and up.