When the Omicron coronavirus variant broke out in the summer of 2022, friends and family of immunologist Bob Seder kept asking him if they should put off getting their COVID-19 booster shots in favour of waiting for the new Omicron-tailored vaccine to go on sale. He urged them to go quickly, as reported by Nature.
Seder, acting chief of the Vaccine Immunology Program at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, suspected that the effectiveness of a new booster would be blunted by a quirk of the immune system known as imprinting — the tendency for someone’s initial exposure to a virus to bias their immune response when they meet the same virus again.
Imprinting was first observed decades ago, in people with influenza.
Their immune systems responded to a new circulating strain by producing antibodies tailored to their first flu encounter.
In some cases, this led to a poorer ability to fight off the new strain.
Members of the older generation, exposed in their youth to a flu strain that closely matched the deadly H1N1 pandemic strain, had a more robust immune response than did younger adults, whose first exposure was to a mismatched strain.
A crop of studies is now showing how imprinting is shaping people’s response to SARS-CoV-2.
Furthermore, even exposure to Omicron itself doesn’t seem to help update the imprinted response of people previously infected with an older strain, which might explain why they can be reinfected.
It’s now relatively easy to update mRNA vaccines to match a new strain, but imprinting suggests that these tailored vaccines might not significantly improve protection against infection.
And although they are clearly able to prevent serious illness, this puts a dampener on the hope that variant-tailored boosters will markedly reduce transmission of the virus.
“You’re better off having some immunity, no matter what it is,” says Katie Gostic, an evolutionary biologist at the University of Chicago, Illinois.
What’s more, there are hints that, in some people at least, the immune system can adapt, raising the possibility of improving immune responses.
Imprinting equips the immune system with a memory of an invader that helps it prepare to do battle again.
The snag comes when the immune system encounters a similar, but not identical, strain of a virus.
In this case, rather than generate new, or ‘naive’, B cells to produce tailored antibodies, the memory-B-cell response kicks in.
They might offer some protection but are not a perfect fit for the new strain.
Imprinting was first observed in 1947 by Jonas Salk and Thomas Francis, the developers of the first flu vaccine, together with another scientist, Joseph Quilligan1.
Researchers have only recently demonstrated how strongly this process can influence immunity.
“We saw this really remarkably clear pattern that you seem to be much more susceptible, at least to severe infection, if you had been imprinted in childhood to a mismatched subtype,” says Gostic.
Boyton and her colleagues reached this conclusion by studying immunity in a large group of healthcare workers at several London hospitals.
Their first study3, conducted before Omicron had emerged, looked at the responses of certain facets of the immune system — including antibodies and B and T cells — in individuals who had received two vaccines.
Some of them had been infected before their jabs and others after.
Last June, she and her colleagues published a follow-up study4 looking at immunity in a group of people who had contracted an Omicron infection after triple vaccination, but who had various COVID-19 infection histories.
Again, they saw a variety of responses indicating imprinting from previous exposure.
For example, even in people whose first COVID-19 infection was with Omicron, the antibodies were a better match to the original strain — against which they had been vaccinated — and to the older Alpha and Delta strains.
This idea is backed up by a study5 published last month by Yunlong Cao at Peking University in Beijing.
By contrast, those without a previous vaccination made antibodies that specifically matched Omicron.
He expects this effect to be even more pronounced with the newer Omicron subvariants, such as XBB.
But the immune system has some tricks that could help to counteract the effect of imprinting, says Laura Walker, chief scientific officer and co-founder of antibody-focused pharmaceutical company Invivyd, based in Waltham, Massachusetts.
Walker and her colleagues tracked antibody responses in mRNA-vaccinated individuals for up to six months after they had contracted Omicron, and found that at least a subset of the B cells was altered so that they started to produce antibodies matching Omicron6.
The transformation occurs in transient structures in the lymph nodes and bone marrow called germinal centres.
Those B cells then go on to produce more-effective antibodies.
Key questions are why that is and how to encourage this new response.
Although affinity maturation helps to align existing B cells with a new foe, researchers have also looked at whether the immune system can deploy entirely new B cells when faced with a new infection.
Immunologist Gabriel Victora at the Rockefeller University in New York City developed a technique that tracks cells and their descendants in mice, to figure out which antibodies came from which B cells.
His results8, published this month, showed that when mice previously vaccinated with the original SARS-CoV-2 strain were boosted with that strain, more than 90% of the antibodies produced were derived from pre-existing B cells.
Walker says that it’s unclear how this translates into longer-term protection.
For that to occur, the new B cells would need to mature into antibody-producing plasma cells in the bone marrow, and it’s not clear whether the immune system retains these newer plasma cells.
Although antibody studies reveal the telltale signature of imprinting, Gostic says, there is little evidence that those signatures affect people’s susceptibility to illness.
Boosters introduced in Europe last September targeted the original strain and the BA.1 Omicron variant; the United States has rolled out boosters aimed at the BA.5 Omicron variant.
The vaccines certainly boost antibody levels, but the antibodies produced are not Omicron specific and are unlikely to offer significantly increased protection against Omicron infection9,10.
So what does this mean for our current vaccines?
But, she says, now that most people are protected, scientists should focus on finding vaccines that can overcome imprinting, to halt the spread of the virus, not just the severity of the disease.
“Now we’re in a slightly different place, we’ve got to think slightly differently.”
Instead, Seder is looking at nasal vaccines, which he thinks could be more effective against variants than injected vaccines.
Spraying a vaccine directly into the nose could induce mucosal immunity — an immune response in the cells that make up the lining of the respiratory system and other mucous membranes.
The antibody response here is prolific and designed to thwart virus entry.
A study11 published last year showed that the antibody response produced by injected vaccines bypasses the antibody cascade that mucosal immunity induces, whereas a breakthrough infection does induce this response.
Adjuvants have been shown to alleviate imprinting in vaccination against flu13.
Imprinting is often presented as a problem, but it’s a fundamental part of immune memory that delivers a lightning-fast response to a viral invader, without having to start from scratch.
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