In the summer of 2022, when the Omicron variant of the coronavirus was widespread, friends of immunologist Bob Seder and his circle of family members would ask him if they were postponing their COVID-19 boosters and waiting for the new Omicron-tailored vaccine to become available. He said don’t delay.
Seder, acting director of the vaccine immunology program at the U. S. National Institute of Allergy and Infectious Diseases. The U. S. Department of Health and Drug Administration in Bethesda, Maryland, suspected that the effectiveness of a new booster would be tempered by a quirk of the immune formula known as fingerprinting: the tendency for someone first to all disclose a virus to skew their immune reaction when they encounter the same virus again.
The fingerprint was first noticed decades ago on other people with influenza. Its immunological formula responded to a new circulating strain by generating antibodies adapted to its first encounter with influenza. In some cases, this has led to a decreased ability to combat the new strain.
The phenomenon is possibly due to some observations from the past, such as the strangely higher mortality among young adults during the 1918 influenza pandemic. Members of the older generation, exposed in their young to an influenza strain that largely matched the fatal pandemic H1N1 strain, had a physically more powerful immune reaction than younger adults, whose first exposure was to an incompatible strain.
Now, a series of studies shows how the fingerprint shapes other people’s reaction to SARS-CoV-2. For example, other people who were infected with the first strain or the upcoming alpha or beta strains develop various immune reactions to the next Omicron infection, depending on which strain they have. were exhibited for the first time.
Also, even exposure to Omicron itself doesn’t seem to help update the published reaction of other people who in the past became inflamed with an older strain, which could explain why they can flare up again.
It’s now relatively easy to upgrade mRNA vaccines to fit a new strain, but the impression suggests that those tailored vaccines might not particularly cover against infection. And while they are obviously capable of preventing serious disease, it holds back hopes that the variant targeted boosters will particularly reduce transmission of the virus.
Still, the researchers agree that variant-compatible boosters are worth getting because they still provide some immunity, and that fingerprinting may not make COVID-19 more severe than it would be in a user with no prior exposure. “It’s better to have some immunity, whatever it is,” says Katie Gostic, an evolutionary biologist at the University of Chicago, Illinois.
In addition, there are indications that, at least in some people, the immune formula would possibly adapt, expanding the choice of immune responses.
The print equips the immune formula with an invading memory that helps it prepare to fight again. The main players are memory B mobiles, which are generated in the lymph nodes when the frame is first exposed to a virus. These mobiles then monitor the same enemy in the bloodstream, able to expand to plasma mobiles that then produce antibodies. The challenge occurs when the immune formula encounters a similar, but not identical, virus strain. In this case, instead of generating new B mobiles or “naïve mobiles” to produce adapted antibodies, the mobile reaction reminiscent B is activated. This leads to the production of antibodies that bind to the characteristics discovered in the old and new strains, called cross-reactive antibodies. It does not adapt perfectly to the new variety.
The fingerprint was first observed in 1947 by Jonas Salk and Thomas Francis, the developers of the first flu vaccine, along with another scientist, Joseph Quilligan1. They found that other people who had already had the flu and were later vaccinated opposed to the existing circulating strain, produced antibodies opposite to the first strain found. Francis gave the phenomenon the ironic call of “original antigenic sin”, today the highest scholars prefer to call it a footprint.
Researchers have recently shown how this procedure can influence immunity. In 2016, Gostic published an epidemiological study2 that showed that impregnation was more than just a curiosity. It analyzed knowledge of two pandemics of avian influenza A, caused by H5N1 in 2009 and H7N9 in 2013. Both strains share some characteristics with seasonal influenza strains, but originate on opposite sides of the influenza evolutionary tree. “We’ve noticed this remarkably transparent trend that you appear to be much more susceptible, at least to a serious infection, if you had published in formative years to an incompatible subtype,” Gostic says.
For SARS-CoV-2 too, “your combined infection history and vaccination history imprint your next immune reaction when you see the live virus,” says immunologist Rosemary Boyton of Imperial College London. Boyton and his colleagues came to this conclusion by reading immunity at a giant health care organization at several London hospitals.
Their first study3, conducted before the appearance of Omicron, tested the responses of certain aspects of the immune formula — by adding antibodies and B and T cells — in Americans who had won two vaccines. Some of them had become inflamed before the bites and others after. Researchers found that a person’s immunity to infection with subsequent strains depends largely on their past infections or vaccines. “Some combinations offer greater coverage compared to a close variant than others,” says Boyton.
Last June, she and her colleagues published a follow-up study4 looking for immunity in an organization of others who had contracted Omicron infection after a triple vaccination, but who had a varied history of COVID-19 infection. Again, they saw a variety of responses indicating the imprint of a past exposure. For example, even in other people whose first COVID-19 infection with Omicron, the antibodies matched the original strain more, unlike the one they had been vaccinated with, and with the older alpha and delta strains.
For those who in the past had become inflamed with the original strain and then were vaccinated (with a vaccine designed to fight that strain), the next infection with Omicron did not at all reduce their ability to create antibodies suitable for Omicron. This is a sign clara. de imprint, Boyton says, and probably explains why Omicron reinfections aren’t all that unusual, although, for most people, even a published reaction is enough to prevent serious illness.
This concept is supported by a study5 published last month through Yunlong Cao of Peking University in Beijing. He found that other people who had been vaccinated with the original strain and then contracted an Omicron infection produced antibodies that commonly cross-reacted with either strain, however, they are rarely expressed to Omicron himself. Conversely, those who had not been vaccinated before produced antibodies that particularly matched Omicron. Cao says that as the two strains diverged from each other, the proportion of antibodies capable of neutralizing the strain of the moment decreased. He expects this effect to be even more pronounced with new Omicron subvariants, such as XBB.
But the immune formula has some tricks that can help counteract the effect of fingerprinting, says Laura Walker, clinical director and co-discoverer of the Waltham, Mass. -based pharmaceutical company Invivyd. Memory B cells can mutate, to some extent, when exposed to a new strain, generating greater antibody compatibility in a procedure known as affinity maturation. Walker and colleagues tracked antibody responses in mRNA-vaccinated Americans up to six months after contracting Omicron and found that at least a subset of B cells were altered so that they began generating antibodies that matched Omicron6. Boyton that affinity maturation can lead to adjustments in immune repertoires over time, But it’s not yet clear to what extent this happens after multiple vaccines.
The transformation occurs in brief structures in the lymph nodes and bone marrow called germinal centers. “You can think of it as a training ground, where our immune cells are trained to get even better,” says Ali Ellebedy, an immunologist at the University of Washington. in St. Louis, Missouri. These B cells then produce more effective antibodies.
Last September, Ellebedy reported7 the effects of one in which his team collected B cells from germ centers from volunteers who won a booster vaccine targeting the original SARS-CoV-2 strain or Omicron.
In either case, even when the original strain was not provided at the recall, the antibodies that detected the original strain were dominant. But, for Omicron’s withdrawal, Ellebedy says, “we were able to stumble upon a very small fraction of cells that responded in particular to Omicron. “This suggests that fingerprinting absolutely doesn’t cancel out responses to the new strains: the team didn’t localize this effect in all individuals. The key questions are why and how to inspire this new response.
While affinity maturation is helping to align existing B cells with a new enemy, the researchers also looked at whether the immune formula can deploy entirely new B cells in the face of a new infection. Immunologist Gabriel Victora of Rockefeller University in New York developed a strategy that tracks cells and their descendants in mice, which antibodies they got to from which B cells.
Their results8, published this month, showed that when mice vaccinated in the past with the original SARS-CoV-2 strain gained a boost with this strain, more than 90% of the antibodies produced came from pre-existing B cells. Animals with the Omicron strain replaced that, Victora explains: 25 to 50 percent of the antibodies came from new B cells, and they neutralized Omicron more than the old recycled antibodies.
Walker says it’s unclear how that translates into longer-term protection. For this to happen, the new B cells would have to mature into antibody-producing plasma cells in the bone marrow, and it’s unclear whether the immune formula maintains them. new plasma cells.
Although antibody studies reveal the telltale signature of the fingerprint, Gostic says, there’s little evidence that those signatures indicate other people’s susceptibility to the disease. Even if protection decreases, Boyton says, “there’s no evidence that it causes harm, worsens the response system, or makes it sicker” compared to other people who aren’t vaccinated or haven’t been infected.
Gostic prefers to look on the bright side: Instead of diminishing the overall response, he says “you have some kind of superpower if you’ve been exposed to anything that fits. “
But it turns out the footprint has dashed hope that introducing variant-targeted mRNA boosters will offer greater coverage against infection than sticking to the original vaccine. Reinforcements brought to Europe last September targeted the original strain and the BA. 1 Ominon variant. ; The United States has deployed reinforcements for the BA. 5 Omicron variant. Vaccines increase antibody levels, but the antibodies produced are not expressed to Omicron and are unlikely to provide particularly improved coverage against Omicron infection9,10.
So what does this mean for our existing vaccines? Boyton says they are “brilliant” in their ability to protect themselves from serious illness. But, he says, now that most people are protected, scientists deserve to focus on finding vaccines that can trump the footprint, to prevent the spread of the disease. virus, not just the severity of the disease. ” Now we are somewhere else, we have to think a little differently. “
Seder that vaccines will want to replace if they want to restrict infection and transmission, rather than simply sparing you death. He says one technique would be to use live vaccines, which would persist in the framework for five to 10 days and could produce a more effective response. But live vaccines pose greater risks, especially for vulnerable people, because of the risks of even a weakened virus multiplying.
Instead, Seder is reading nasal vaccines, which it says are more effective compared to variants than injected vaccines. Spraying a vaccine directly into the nose can also induce mucosal immunity, an immune reaction in the cells that make up the lining of the respiratory formula. and other mucous membranes. In an herbal infection, the mucous membranes are the first barrier a virus will encounter. The antibody reaction here is prolific and designed to prevent the virus from accessing. Its very strength can also create greater coverage, including preventing infection and transmission. A study11 published last year showed that the antibody reaction produced through injected vaccines crosses the antibody cascade induced through mucosal immunity, while advanced infection induces this reaction.
Seder is now comparing nasal and mRNA vaccines in animals to see if they can react to Omicron. Data on how these vaccines work in humans are scarce and mixed. In October, a phase I clinical trial of a vaccine was developed through Astrazeneca and the University of Oxford, United Kingdom, administered as a nasal spray, reported mucosal antibody reactions only in a minority of participants and weaker systemic reactions than those achieved with intramuscular vaccination12.
Another technique is to use adjuvants: ingredients added to vaccines that stimulate the immune response. Adjuvants have been shown to attenuate the footprint in influenza vaccination. 13 So far, their effect on fingerprinting in COVID-19 has not been proven.
The ideal immune reaction is strong and broad, either to disarm the footprint and combat a wider diversity of viruses and variants, Boyton says. A vaccine against SARS-CoV-2 and all its relatives, a coronavirus vaccine, would induce a wider variety of antibodies that target various parts of the virus. Such a vaccine can prevent the virus from mutating enough to evade the immune formula and, in the end, may be the key to controlling pandemics in the long term. The search for such a vaccine is ongoing.
Imprinting presents itself as a problem, but it is a basic component of immune memory that provides an ultra-fast reaction to a viral invader, without having to start from scratch. “To me,” says Victora, “it means the immune formula is wise enough to cover its bases. “
Nature 613, 428-430 (2023)
doi: https://doi. org/10. 1038/d41586-023-00086-1
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