Covid Boosters Can’t Outpace New Mutations. Here’s Why They Still Work

The latest vaccines are designed to target XBB.1.5, the dominant variant throughout much of 2023—until now.

Updated vaccines against Covid-19 are coming, just as hospitalizations and deaths due to the virus are steadily ticking up again.

Today, the US Food and Drug Administration authorized new mRNA booster shots from Moderna and Pfizer, and a panel of outside experts that advises the Centers for Disease Control and Prevention voted to recommend the shots to everyone in the United States ages 6 months and older. Once Centers for Disease Control and Prevention director Mandy Cohen signs off on the recommendations and the vaccines are shipped, people can start getting the boosters.

The recommendation is projected to prevent about 400,000 hospitalizations and 40,000 deaths over the next two years, according to data presented at the meeting by CDC epidemiologist Megan Wallace.

This year’s mRNA vaccines are different from the 2022 booster in a key way. Last year’s shot was a bivalent vaccine, meaning it covered two variants: the original one that emerged in China in 2019, plus the Omicron subvariant BA.5, which was circulating during much of 2022. This fall’s booster drops the original variant, which is no longer circulating and is unlikely to return. It targets just the Omicron subvariant XBB.1.5, which was dominant throughout much of 2023.

Pfizer and Moderna’s vaccines work by introducing a tiny piece of genetic material called messenger RNA, or mRNA, that carries instructions for making SARS-CoV-2’s characteristic spike protein. Once it is injected, cells in the body use those instructions to temporarily make the spike protein. The immune system recognizes the protein as foreign and generates antibodies against it. Those antibodies stick around so that if they encounter that foreign invader again, they will mount a response against it.

Since the start of the Covid-19 pandemic, the virus has acquired new mutations in its spike protein and elsewhere. These mutations result in new variants and subvariants that diverge from the original virus. When enough mutations accumulate, these new versions can more easily evade the antibodies created by previous vaccine doses or infections.

The constantly evolving nature of the virus is the reason health regulators decided last year to update the original mRNA vaccines, which were designed against the version of the virus that first appeared in 2019. This year, once again, the virus has changed enough to warrant an updated booster.

In June, an advisory committee to the FDA recommended that this fall’s booster be a monovalent vaccine—targeting only the then-dominant XBB.1.5 subvariant.

At that meeting, committee members reviewed evidence suggesting that the inclusion of the original variant may hamper the booster’s effectiveness against newer offshoots. “The previous bivalent vaccine contained the ancestral spike and thus skewed immune responses to the old spike,” says David Ho, a professor of microbiology at Columbia University whose research, which is not yet peer-reviewed, was among the evidence the FDA panel reviewed. “This is what we call immunological imprinting, and it results in lack of immune responses to the new spike.” He thinks taking out the old variant should optimize the immune response.

But over the past few months, even newer Omicron offshoots have arrived. Currently, EG.5.1, or Eris, is the dominant one in the United States, United Kingdom, and China. Meanwhile, a variant called BA.2.86, or Pirola, has been detected in several countries. Pirola has raised alarm bells because it has more than 30 new mutations compared to XBB.1.5.

Even though the new boosters were formulated against XBB.1.5, they’re still expected to provide protection against these new variants. “The reason is, while antibodies are important in protection against mild disease, the critical part of the immune response that’s important for protecting against severe disease is T cells,” says Paul Offit, a professor of vaccinology at the University of Pennsylvania and member of the FDA’s vaccine advisory committee.

These cells are a different part of the immune response. Unlike antibodies, which neutralize a pathogen by preventing it from infecting cells, T cells work by eliminating the cells that have already been invaded and boosting creation of more antibodies. Both the Moderna and Pfizer-BioNTech Covid vaccines produce long-lasting T cells in addition to antibodies.

It’s why, Offit says, when the Omicron wave hit in late 2021 and peaked in January 2022, the US didn’t see a dramatic increase in hospitalizations and deaths even as cases rose significantly: People’s T cells kicked into gear, even when their antibodies didn’t recognize the Omicron variant.

“In some ways,” says Offit, when it comes to vaccine booster development, “it almost doesn’t matter what we pick to target” because the coronavirus has yet to evolve away from T cell recognition. “Everything works.”

Scientists think T cells are able to protect against severe Covid because they’re recognizing parts of the virus that have remained unchanged throughout the pandemic. “I suspect that as we continue to vaccinate, there are some conserved regions [of the virus],” says Jacqueline Miller, Moderna’s head of infectious diseases. “So even with the accumulation of mutations, we’re still building on previous immunity.”

People who have hybrid immunity—that is, have had a Covid infection and have also been vaccinated—seem to have the best immune responses to new variants, she says, which suggests that previous exposure shapes and improves immune responses to new variants. Preliminary studies show that antibodies generated by previous infections and vaccinations should be capable of neutralizing Pirola.

Earlier this month, Moderna issued a press release saying that clinical trial data showed that its updated booster generated a strong immune response against Pirola, as well as the more prevalent Eris variant.

In a statement to WIRED, Pfizer spokesperson Jerica Pitts said the company continues to closely monitor emerging variants and conduct tests of its updated monovalent booster against them. Data presented at Tuesday’s CDC meeting showed that Pfizer-BioNTech’s updated booster elicited a strong neutralizing antibody response against both Eris and Pirola.

The FDA expects that Covid-19 vaccines will continue to be updated on an annual basis, unless a completely new variant emerges that requires a different approach. “We will always be a little behind the virus,” says Ho. “In this instance, we won’t suffer too much, but that might not be the case going forward. Surveillance is imperative.”

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