A health-care worker in Chicago, Illinois, administers a COVID-19 vaccine aimed at the Omicron subvariant.Credit: Scott Olson/Getty

Booster shots against current SARS-CoV-2 variants can help the human immune system to fight variants that don’t exist yet.

That’s the implication of two new studies1,2 analysing how a booster shot or breakthrough infection affects antibody-producing cells: some of these cells evolve over time to exclusively create new antibodies that target new strains, whereas others produce antibodies against both new and old strains.

The findings provide reassurance that new vaccines targeting the Omicron variant will provide some benefit. The utility of these vaccines — which US regulators approved on 12 October for children as young as 5 — had been called into question by findings that the immune system has trouble pivoting from one variant to another. “All of that is really showing the brilliance of the immune system of making guesses about what variants are going to look like,” says Shane Crotty, a virologist at the La Jolla Institute for Immunology in California.

The studies were published last month on the preprint server bioRxiv. Neither has yet been peer-reviewed.

After the Omicron variant emerged last November and began infecting vaccinated people, pharmaceutical companies rushed to develop Omicron-specific booster shots. In August, the US Food and Drug Administration approved ‘bivalent’ shots that target the BA.4 and BA.5 variants and the original strain. In September, European regulators approved a booster against the BA.1 Omicron variant.

But the usefulness of these formulations has been called into question by recent data on a phenomenon known as immune imprinting. The central players are the immune cells called B cells, which “are basically antibody factories with the lights turned off”, Crotty says. Each B cell produces only one type of antibody. After encountering an unknown pathogen, the immune system activates pre-existing B cells whose antibodies recognize an antigen that most closely matches the new intruder. The human body also has a limited number of B cells in reserve that can create entirely new antibodies against the specific new threat.

Imprinting, also called ‘original antigenic sin’, refers to the immune system’s tendency to fixate on the first version of a pathogen that it encounters, regardless of subsequent attacks by different variants. Researchers have long worried that the immune system could be imprinted with the original version of SARS-CoV-2, which could explain why variants, such as Omicron, nimbly evade mRNA vaccines developed against the original SARS-CoV-2 strain.

Because of the potential impact of imprinting, the immune system’s reaction to bivalent boosters has also been unclear. If the immune system were to adapt to respond to new variants, it could create new B cells that produce entirely new antibodies against Omicron. But it might instead adapt its existing, imprinted B cells. Immunologist Ali Ellebedy at Washington University in St. Louis, Missouri, likens it to the difference between “drafting new soldiers in our army instead of retraining the old veterans”.

To find out, Ellebedy’s team, which receives funding from Moderna, a COVID-19 vaccine maker based in Cambridge, Massachusetts, collected lymph-node samples from 26 people and bone-marrow samples from 15 people; all had received the original vaccine and Moderna’s booster against Omicron BA.1. Analysis showed that most of the participants’ B cells recognized both the original and Omicron strains. Study participants also had a few new types of Omicron-specific B cell. These responses imply that the cells had overcome imprinting and adapted to a new foe.

In the second preprint, scientists collected samples from six people who became infected with Omicron despite having received the original vaccine. The team found that, one month after Omicron infection, nearly 97% of participants’ antibodies targeting SARS-CoV-2 still bound the original strain better than Omicron BA.1. But six months after infection, nearly half of participants’ B cells produced antibodies that bound Omicron BA.1 better than the original strain — showing that the immune system continued to adapt long after the infection had passed.

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“It’s good to see evidence that, even when it’s imprinted, the immune system is adapting in ways that are helpful in redirecting to the newer variant,” says Jesse Bloom, a computational virologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, who was a co-author on the second paper.

He says that designing boosters that target circulating strains might be worthwhile, even if the virus evolves to avoid them. That’s because any strain that arises will be genetically closer to the one just before it than to the original strain and the vaccines against it.

At this point, Crotty says, it seems unlikely that anyone will discover a “magical” part of the virus that can’t mutate to avoid the immune system. Now that the virus has infected billions of people4, it’s had many chances to devise ways to dodge our defences.

But he says that the papers are both reassuring, showing that the immune system can be just as creative as the virus. “The immune system has [had] millions of years to realize that if one virus shows up, there’s a decent chance that in the near future some relative of that virus will show up,” he says. “Having a diversity of ways to respond is of value.”

Michel Nussenzweig, an immunologist at Rockefeller University in New York City, is less convinced. He points out that Bloom’s paper had a very small sample size and did not show that the new antibodies could actually block the new variants, just that they could bind to it. His own research3 has found that infection by Omicron only drove the evolution of antibodies specifically against that variant, not against all SARS-CoV-2 strains.

The authors of all the papers conclude that efforts to develop ‘variant-proof’ boosters should focus on ways to make more diverse antibodies, rather than antibodies against individual strains. “Hopefully we shouldn’t have to keep doing boosters for very long,” Crotty says. “But the virus is in the driver’s seat.”