Scientists race to answer the question: Will vaccines protect us against omicron?

Researchers in Botswana and South Africa just detected the omicron variant a few weeks ago, but already many scientists are predicting that the efficacy of the vaccines will likely take a hit, probably a big hit, when it comes to stopping infections of omicron. And more breakthrough infections will likely occur if (and that's a big if) omicron spreads here in the U.S.

At the same time, there's hope that vaccines will still offer good protection against severe disease and hospitalization, especially with a third dose.

A supermutant version from a lab could hold answers

What's the reason for the strong current of pessimism?

The answer lies in a study published back in September which, in many ways, predicted the emergence of a variant like omicron — that is, a variant with an exceptionally large number of mutations. The study also offers critical insights about how well vaccines will work against omicron.

In the study, published in Nature, the scientists were trying to understand how SARS-CoV-2 learns to outsmart people's antibodies — the body's key defense against viral infections.

Paul Bieniasz and his colleagues wondered if SARS-CoV-2 could evolve in a way to completely knock out antibodies' ability to detect and kill the virus. "The goal was to answer the question: Is it possible for SARS-CoV-2 to completely evade neutralizing antibodies?" Bieniasz says.

So he and his team intentionally engineered a supermutant version of the virus — though not the full virus, just a piece of it. Specifically, they focused on the infamous spike portion of the virus, which binds to human cells and is the target of important antibodies. Bieniasz tried to make this spike completely impervious to antibodies.

In essence, they took about 20 mutations and put them all together onto one spike protein, which they call a "polymutant spike mutant." These mutations had already cropped up in several variants around the globe but never all together.

"They are the mutations that individually occur naturally and we combined them," Bieniasz says. And they had been shown to help the virus evade detection by antibodies.

Interestingly, Bieniasza says, the omicron variant has many of the same mutations as this polymutant spike protein. But it has even more mutations, he says. Instead of just 20 mutations on the spike protein, omicron has about 30. "Omicron appears to have certain combinations of mutations that together would confer more pervasive resistance to individual classes of antibodies," he says.

Bieniasz and his team then took antibodies from people who have had two doses of an mRNA vaccine or had a prior COVID infection. They tested these antibodies against the polymutant spike protein. They looked to see if those antibodies could have any ability whatsoever to even partly neutralize it. For all practical purposes, they couldn't.

"This polymutant spike protein was almost completely resistant to the neutralizing antibodies in those two sets of plasmas," Bieniasz says.

"Based on those findings, we expect that omicron will be significantly resistant to antibodies that are circulating in individuals who have convalescence or who have had mRNA vaccines," Bieniasz says. "The magnitude of that loss of sensitivity to those antibodies obviously has to be experimentally determined."

But faith in vaccines is not lost – especially with a booster added in

Scientists all over the world, including those working for vaccine manufacturers, are rushing to figure out what that magnitude will be. For instance, researchers at Pfizer are taking antibodies from people who have had two or three shots of the vaccine and seeing if those antibodies have any neutralization capabilities against omicron.

"We remain cautiously optimistic that after three doses, you will have some meaningful protection," says Dr. Mikael Dolsten, who's the chief scientific adviser for Pfizer.

The hope is that protection against severe disease and hospitalization will hold up, says virologist Jeremy Luban at UMass Chan Medical School. Antibodies are the primary tool your body uses to stop an initial SARS-CoV-2 infection. But even if the effectiveness of your antibodies goes down 10- or 20-fold, "that might still be enough to keep you from going to the hospital," Luban says.

In addition, there are other components of the immune system, such as T cells, which can clear out an infection quickly if one does occur — and thus, help to protect you from serious illness. In general T cells are much less likely to lose effectiveness when the virus mutates than antibodies are. For example, Dr. Antonio Bertolettiand his team at Duke-NUS Medical School have preliminary data showing that T cell activity remains quite high even against a polymutant spike protein similar to the one created by Bieniasz and colleagues. "Conclusion: the picture does not look so terrible for T cells," members of the Bertoletti lab wrote on Twitter.

Finally, there's even more hope that a third shot of an mRNA vaccine — a so-called booster — will work better than two shots, says virologist Pei-Yong Shi at University of Texas Medical Branch in Galveston, who works with Pfizer. First off, he says, the third dose doesn't just return your antibody levels to what they were after the second shot. The level is even higher.

On top of that, the booster can actually help broaden out your defenses so that you can fight off not just one variant of SARS-CoV-2 but many different versions of it. "The booster increases the level of antibodies that can push back against the variants," Shi says. "So that's another advantage to the booster."

In other words, that extra exposure could help the body stay one step ahead of the virus — and even perhaps teach the immune system how to fight off additional variants that could arise in the future.

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