The Covid Virus Keeps Evolving. Why Haven't Vaccines?

Updating the shots to adapt to rapidly changing variants is easier said than done, even with new mRNA technology.

On March 16, 2020, the first volunteer received a shot of Moderna’s then-experimental Covid-19 vaccine, just 63 days after the company had generated a genetic blueprint of the new virus. But Moderna’s rival beat it to the marketplace: Pfizer’s Covid vaccine would be authorized for use in the United States less than a year later, a record-breaking achievement. Previously, the fastest a vaccine had ever been developed was for mumps—which took about four years.

The speed at which both companies were able to deliver their vaccines can be credited to mRNA technology. Instead of using the virus itself to spur an immune response, as older vaccines do, scientists instead spur it using a programmable piece of genetic code called mRNA. The mRNA tells the body to make a version of the coronavirus’s distinct spike protein, so it can make antibodies to neutralize that spike. The mRNA is quickly broken down, but the memory of the spike protein lingers in the immune system, so it’s ready to launch an attack if it encounters it again.

The promise of mRNA technology was its adaptability. Vaccine makers touted its plug-and-play nature. If the virus mutated to evade current vaccines, scientists could simply swap in a new piece of mRNA to match the new version of the virus. But today, despite waves of variants including Delta, Omicron, and the latest threats—Omicron subvariants BA.4 and BA.5—the Covid-19 vaccines and booster shots still target the original virus that was identified in late 2019. Why haven’t variant-specific boosters arrived sooner?

“You’re working with a virus that is rapidly mutating. Each of these variants is around for a few months and then is replaced by a new variant,” says infectious disease specialist Archana Chatterjee, dean of the Chicago Medical School. “This is a race that we are continually behind on.” 

And BA.4 and BA.5 are the fastest movers yet. “This virus has, over the period of these two years, become more and more contagious,” continues Chatterjee, who is also a member of the Vaccines and Related Biological Products Advisory Committee (VRBPAC), an independent panel of experts that advises the US Food and Drug Administration.

While the currently available vaccines have greatly reduced death and hospitalization due to Covid-19, “their effectiveness does appear to wane with time,” said Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, during a June 28 VRBPAC meeting. Initial booster shots helped restore some protection against severe disease, but their effectiveness also seems to fade.

In June, all of these factors led VRBPAC to recommend that vaccine manufacturers update Covid booster shots for fall and winter 2022, tailoring them to the BA.4 and BA.5 subvariants. Chatterjee says the committee made the recommendation based on evidence that these subvariants seem to be driving a new wave of hospitalizations across the US and the UK. The US government intends to buy millions of variant-specific doses for a fall booster campaign.

Jacqueline Miller, senior vice president of infectious diseases at Moderna, says the company recognized early on that they’d have to race to catch up with the virus. The first variants of concern—Alpha and Beta—were identified in late 2020, just as the vaccines were being rolled out. While the original vaccines held up against the Alpha variant, they were slightly less effective against Beta. “That was really what prompted us to go down this road of investigating variant vaccines,” she says.

Miller says it takes Moderna about four to six weeks from the time of generating a new variant’s genome sequence to producing enough vaccine doses to begin human testing. Pfizer’s process is similarly fast.

“The design time to the actual production of the vaccine is still remarkably faster than other vaccines that we're talking about,” says Michael Diamond, a viral immunologist at Washington University in St. Louis who has studied mRNA vaccines. “The variants are just coming faster than we anticipated.”

The late-2020 Beta variant was quickly supplanted by Delta, which took hold in summer 2021 and caused another surge of infections around the world. Both Moderna and Pfizer rushed to test updated shots aimed at the Delta variant. But the companies' original vaccine formulas proved effective against Delta because its spike protein wasn’t all that different from the ancestral version of the virus. When Omicron emerged in November, it had dozens of mutations in its spike protein that allowed it to more easily escape the vaccine. It caused an explosion in Covid cases over the following months.

While the process of updating an mRNA booster goes rather quickly, testing and manufacturing it at scale takes longer. Variant-specific vaccines still need to go through animal and human testing to make sure they’re safe and generate an immune response. The FDA has said that vaccine makers can bypass large trials for updated Covid vaccines and instead test them in smaller groups of volunteers, similar to what’s done for the annual flu vaccine. Then, companies need to study volunteers’ blood to compare the immune response generated by the modified booster to the one generated by the original vaccine. The whole process from start to finish takes Moderna about six months, says Miller.

And that’s not counting the time it takes for FDA authorization, to make the new formula, or to get it to pharmacies and doctor's offices. Miller says she hopes the timeline will get shorter once the first variant-specific booster is out of the gate.

Omicron has stuck around longer than previous variants, which has given both Pfizer and Moderna more time to develop boosters against BA.4 and BA.5, after originally generating candidate boosters against the earlier BA.1 subvariant. On July 11, Moderna announced that its Omicron-specific candidate generated a “significantly higher neutralizing antibody response” against BA.4 and BA.5 than the currently available shot.

Pfizer and BioNTech also said its Omicron booster candidates spurred a better antibody response against the variant than the company’s already-approved vaccine. “For our Omicron-adapted vaccines, we explored a higher dose, which we anticipated may be necessary against the highly transmissible Omicron variant and subvariants,” says Pfizer spokesperson Keanna Ghazvini.

The Centers for Disease Control and Prevention estimates that BA.4 and BA.5 currently make up more than 81 percent of cases in the US. Of course, there’s no guarantee that they will still be the dominant variants come fall. Diamond says even if they aren’t, a booster that targets those versions of the virus will likely still provide better protection than the original formulation. “The reason to give a booster that is different from the original one is to broaden the immune response,” he says. “Some of that greater breadth may actually be able to anticipate new variants, even though your immune system has never seen them.”

But Maria Elena Bottazzi, associate dean of the National School of Tropical Medicine at Baylor University, says it’s not enough to just switch from a booster against the original sequence to an Omicron-specific one. She thinks governments around the world will need to come up with longer-term solutions, especially as people lose interest in getting additional booster doses.

“What we have learned is that as much as the mRNA technology has been very effective and safe, the immunological response is not very durable,” she says. Older vaccine technologies, she says, may be able to provide longer-lasting protection. Bottazzi and her colleagues have developed a low-cost Covid-19 vaccine called Corbevax, which has been approved for use in India and Botswana. Known as a protein subunit vaccine, it uses a tiny, purified part of the spike protein to elicit an immune response. It also includes an adjuvant, an ingredient in some vaccines that helps increase the immune response.

“There's no doubt that mRNA broke the paradigm,” says Bottazzi. “But I don’t think it’s the one and only solution.” The latest Covid-19 vaccine to receive emergency authorization in the US is a protein subunit vaccine, made by Maryland biotech company Novavax.

Labs around the world are also attempting to develop a universal coronavirus vaccine, which would protect against virtually any member of the coronavirus family, including new variants of SARS-CoV-2 that arise.

Even if new boosters do arrive this fall, persuading people to get another shot will be a challenge. Only about 29 percent of people eligible for a second booster dose have received one.

Whether we’ll need a tailored booster shot every time a new variant arises is hard to know, says Chatterjee. It may be that an Omicron booster will be enough to offer protection against variants that emerge in the near future. But beyond that, she says, a big question remains: “How do you get ahead of this virus?”

The Covid Virus Keeps Evolving. Why Haven't Vaccines?

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