To beat Omicron, the race is on to tweak existing vaccines

Experts say that updating available vaccines for the worrisome new variant is not that hard and will still yield safe shots.

Almost exactly a year ago, on December 11, 2020, the U.S. Food and Drug Administration authorized the country’s first COVID-19 vaccine. That Pfizer-BioNTech shot and the ones from other companies that followed have strengthened our collective armor against all the coronavirus variants that have evolved since.

But now scientists fear that the mutations in Omicron alter the virus so significantly that the recipes for the vaccines may need to be adjusted.

As soon as Omicron was characterized in late November, companies rushed to declare that they are on the case. In addition to testing how well their current shots hold up against the new variant; Moderna vowed to “rapidly advance an Omicron-specific booster candidate;” Pfizer said it would have one available by March; and Johnson & Johnson announced it “is pursuing an Omicron-specific variant vaccine.”

Novavax, which has filed for authorization but whose vaccine is not yet available in the U.S., said in a statement that its Omicron-targeted offering will be “ready to begin testing and manufacturing within the next few weeks.”

In some ways, the race to reformulate the shots is striking. “We don’t have many vaccines that we change regularly: measles hasn’t changed, rubella hasn’t changed, hepatitis hasn’t changed,” says Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.

Compared to those more stable pathogens, though, this coronavirus evolves quickly. Experts closely watching Omicron’s spread say drug companies’ efforts to tailor a vaccine to this variant are warranted, because it seems to evade immunity better than prior ones.

“My optimism about Omicron has waned over the past week,” as more—albeit preliminary—data comes in from South Africa, says Vaughn Cooper, professor of microbiology and molecular genetics at the University of Pittsburgh School of Medicine. “The rate of infection [among] previously sick or vaccinated individuals contracting Omicron is really high.”

Rewriting genetic code

Omicron’s ability to infect people who should have immunity likely results from the whopping number of mutations—more than 30—in its spike protein, the part of the virus that helps it enter human cells.

Most concerning are several mutations in what is known as the receptor binding domain, the region of the spike responsible for attaching to our cells, Cooper says. One part of our immune system, its B cells, generate three main types of antibodies that each target a unique section of the spike protein’s surface. Prior variants have had mutations in one or two of these antibody targeting regions, but Omicron has mutations in all three, he notes.

Other variants of concern, especially Beta, have shared some of Omicron’s potentially antibody-evading mutations, but no others have as many, or in the same combinations. “It’s possible that some of the mutations might work in concert with other mutations. Or maybe they cancel each other out. We don’t yet know,” says Katelyn Jetelina, assistant professor of epidemiology at the University of Texas Health Science Center at Houston and the author of the popular Your Local Epidemiologist blog.

The key question is whether the mutations or some combination of them confuse an immune system trained to spot the spike protein, whether from prior vaccinations or from contracting COVID-19.

“Significant alterations in the shape or structure of spike might change how effectively our immune cells neutralize the virus,” says Jill Weatherhead, assistant professor of tropical medicine and infectious diseases at Baylor College of Medicine. She emphasizes, however, that nobody yet knows if that’s the case.

Should changes be needed in the vaccines, the new mRNA vaccines will be easier to modify than most non-COVID vaccines. The process should take only a few months, says Onyema Ogbuagu, a Yale Medicine infectious diseases specialist and a principal investigator of the Pfizer COVID-19 vaccine trials.

The active ingredient in an mRNA shot is genetic code that provides the instructions for human cells to produce the virus’s spike protein. The mRNA is fashioned in a lab from four chemical building blocks called nucleotides. To target new mutations in the spike, you simply remove a few of the old blocks and replace them with new ones, Ogbuagu explains.

Altering the Johnson & Johnson vaccine, where the genetic code is delivered by an adenovirus vector, may be a bit more challenging. But it too fundamentally involves rewriting a bit of code, Weatherhead says.

In a vaccine with a lot of genetic instructions, these alterations would be small, which is why new side effects from refashioned shots are unlikely, Ogbuagu adds. “It’s not creating a new vaccine. It’s more like taking a dress and hemming it to give it a new length,” he says.

Lessons from flu shots

Scientists point to seasonal flu as the model for how to potentially modify COVID-19 vaccines. Each February the World Health Organization uses data from circulating influenza in the Southern Hemisphere, combined with laboratory studies, to make an educated guess about which flu strains will dominate the following season.

Licensed vaccine manufacturers need only prove to the FDA that changes they make to target these strains trigger an adequate number of antibodies to fight them. Companies can test this in a small group of people. They are not required to conduct large clinical trials each year, as they must before getting approval for a novel vaccine.

Updated guidance from the FDA issued in February 2021 outlines similar steps for COVID-19 variants, a process known in the industry as “plug and play.” Manufacturers who tweak their shots can test immune response in a modest number of people—likely several hundred, experts expect. The guidance recommends including people who have various COVID-19 vaccine histories, from no prior shots to all recommended boosters. But it doesn’t mandate testing the vaccine in all age groups, such as children or older people.

Should a strain change be needed for COVID-19, the FDA will need to move even faster than it does for influenza. “With flu they have six months to develop new shots; with the coronavirus pandemic, they’ll need it now. But no shortcuts will be taken,” Osterholm insists.

Companies will have to follow their current manufacturing processes identically for any tweaked shot they put forward. This is the key to keeping them safe, he says. Large numbers of unexpected side effects in flu shots haven’t turned up since the swine flu vaccine in 1976, when dozens of people developed the neurological disorder Guillain-Barré syndrome. Osterholm attributes that to shifts in how the flu shots were manufactured, not to the change in strain.

To gauge whether Omicron will require changes in our vaccines and boosters, scientists in the U.S. are closely watching the variant’s behavior in other countries, including Israel and the United Kingdom, where nationalized health systems allow them to quickly link vaccination records with COVID-19 cases.

“Throughout the pandemic, these countries have been turning around large data sets in seven to 10 days,” Osterholm says. Information from South Africa, where the variant is widely spreading, will also reveal whether Omicron has infected a higher percentage of seriously ill patients who were vaccinated compared to Delta.

Tests on the blood of vaccinated people are also used to determine how well antibodies might take down Omicron. These preliminary lab studies have already shown that three doses of Pfizer’s vaccine are effective against the variant, the company says. But these “viral neutralization assays” have limited value, Osterholm says. “This can potentially demonstrate that there is a substantial decrease in neutralization, but you still have to translate that to clinical care,” he says.

Even if the original vaccines are found to be less effective against Omicron, they may still prove potent enough, especially because vaccines stimulate our immune system’s T-cells as well as the antibody-producing B-cells. The problem is they don’t mobilize as quickly. “This cellular immune response takes time, so more people might get sick while it is gearing up—what we’ve been calling breakthrough infections,” Cooper says.

Still, getting one of the currently available shots, including all recommended boosters, “is the best tool we have now,” so everyone should do that, Weatherhead says.

Eventually, manufacturers might come up with a universal vaccine, one that would be effective against all of the variants that might arise. The idea is that it would target several essential features of the SARS-CoV-2 virus, rather than only one, around which the virus could evolve, Cooper says.

This technique may once have seemed pie-in-the-sky, Cooper says. But the success of the mRNA technology and the amount of science learned about virus-host interactions from this pandemic “has bolstered the idea of universal vaccines against major viruses like coronavirus and flu enough that we could see clinical trials start within a few years.”

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