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With Covid-19 vaccines, the world hopes to beat back the virus that causes the disease. But some scientists are increasingly concerned that, because of a quirk of our own biology, future iterations of the vaccines might not always be quite as effective as they are today.

The concerns stem from a phenomenon that is known as imprinting, sometimes called original antigenic sin, which is believed to affect how we respond to some pathogens.

In short, when your body is introduced to a particular threat for the first time — either through infection or a vaccine — that encounter sets your immune system’s definition of that virus and what immune weapons it needs to detect and protect against it in the future.

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That imprint can be helpful. In the 2009 H1N1 flu pandemic, elderly adults were protected by immune responses they’d generated more than half a century earlier, in childhood, through encounters with a related virus. But it can also interfere with your body’s ability to mount responses against strains that have evolved from the one you were first exposed to.

In the case of Covid, some scientists are concerned that the immune system’s reaction to the vaccines being deployed now could leave an indelible imprint, and that next-generation products, updated in response to emerging variants of the SARS-CoV-2, won’t confer as much protection.

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Michael Worobey, who was been involved in groundbreaking research on imprinting with influenza, said he worries the responses to first-generation Covid-19 vaccines will prove to be “a high-water mark” for people’s immune responses to these inoculations.

“I do think it’s something that we need to be thinking about,” Worobey, a professor of evolutionary biology at the University of Arizona, told STAT. “We might actually see lower efficacy five years from now, if people are still locked into recalling the response to the first [SARS-2] antigen that they saw.”

Sarah Cobey, an associate professor of computational biology at the University of Chicago, shares his worry. “As long as we have competition between old antibody responses and new antibody responses … then it seems like exactly the right sort of environment to see these phenomena,” Cobey said.

“I can’t think of a reason that should be restricted to influenza,” she added.

Not everyone in the conversation is convinced there will be a problem, though.

Vineet Menachery is a coronavirus expert at the University of Texas Medical Branch in Galveston, one of the smallish community of researchers who were studying coronaviruses before the Covid-19 pandemic hit. He noted that the SARS-2 spike protein — the protein that projects from the virus’ surface, giving it the appearance of wearing a crown — doesn’t have as much wiggle room to change as the hemagglutinin proteins that sit atop of flu viruses.

Both the spike and the hemagglutinin proteins are the means by which their respective viruses attach to the cells they are trying to infect; in the case of SARS-2 viruses, attachment occurs via a receptor known as ACE2. But influenza viruses mutate at a far faster rate than coronaviruses and they have much more leeway to change — mutational space, Menachery called it — without impeding its functionality.

“The changes that we see in the [SARS-2] variants aren’t whole-hog changes,” he said.

Imprinting is one of the reasons why flu vaccines aren’t as protective as we’d like them to be. Flu is a notorious shape-shifter and its constant alterations allow influenza viruses to evade immune system protections generated by either vaccination or previous infections. People who first encountered H1N1 viruses, for instance, never get as much protection from the H3N2 component of a flu shot as they do from the H1N1 part.

“Basically, I think of original antigenic sin as some sort of hierarchy in immune memory, meaning you preferentially boost what you’ve seen before, at the expense of developing responses to the new stuff,” Cobey said. “It could impact the effectiveness of [Covid] vaccine going forward.”

Scott Hensley, a sometimes collaborator of Cobey’s, has actually seen some evidence of coronavirus imprinting in his research. An associate professor of microbiology at the University of Pennsylvania, Hensley and colleagues were working to develop Covid-19 antibody tests in the early days of the pandemic. The work involved studying using blood samples from people who contracted Covid. They compared the post-infection samples to blood drawn from the same individuals prior to the pandemic.

In comparing the before and after blood samples, they saw in the post-infection sample a “dramatic” rise in antibodies to one of the humans coronaviruses that is among the causes of the common cold. It was a virus called OC43, which is in the same coronavirus family as SARS-2, as well as the viruses that cause SARS and MERS.

In other words, Covid infection actually boosted the immune system’s protection against a different virus, one that the immune system already knew.

Still, Hensley isn’t worried about imprinting — or at least not among people who have been vaccinated with mRNA vaccines. The very strong immune response generated by the Moderna and the Pfizer-BioNTech vaccines should override any imprinting impacts as SARS-2 mutates, he said. Hensley worries, though, that people whose immunity to the virus comes from infection, not vaccination, might have more difficulty handling variant viruses because of imprinting effects.

David Topham, an immunologist at the University of Rochester Medical Center and director of the New York Influenza Center of Excellence, also envisages that possibility.

He noted that, in the earliest stages of SARS-2 infection, the immune system mounts a response to a portion of the spike protein called S2. Later, the immune system focuses its attention on other parts of the spike, notably the part of the protein that attaches the virus to cells it invades, known as the receptor binding domain.

It’s not yet known if the early focus on S2 — which doesn’t change much from virus to virus — will blind the immune system to the changes elsewhere in the spike protein, the changes updated vaccines would be trying to teach the immune system to respond to, Topham said.

Topham doesn’t think this will be a problem in vaccinated people, because of the way the vaccines in use have been designed. The spike proteins they trigger production of appear to hide the S2 region, he said. The immune system can’t fixate on something it doesn’t see.

For people whose immunity comes from infection, Topham sees three possible scenarios. “It can be a problem, because the immune cells specific for S2 outcompete immune cells against other components of the spike protein that you really need in order to get protection. It can be inconsequential in that eventually the responses to the other parts of the protein catch up and it doesn’t matter. Or it could actually be a benefit because it gets the immune system revved up more quickly.”

Topham is not alone in speculating that an original Covid vaccine with a booster targeting variant viruses could, in fact, lead to a stronger immune response.

“You might actually end up with an immune response that is broader,” said Florian Krammer, a professor of vaccinology at the Icahn School of Medicine at Mount Sinai Hospital in New York.

Krammer used as an example research done by scientists at the Finnish Institute for Health and Welfare and University of Turku on vaccination against H5N1 bird flu. H5N1 vaccine that don’t contain adjuvants — boosting compounds — appear to generate poor immune responses. But in a paper published in the journal Vaccine, the researchers reported that a priming and boosting regimen that used two different H5N1 vaccines, made with different strains of the virus, induced a strong and long-lasting response.

We may find out whether this is going to be a problem sooner than you’d think. Moderna is working with the National Institute of Allergy and Infectious Diseases — which helped it design its original Covid vaccine — to test an updated version of its vaccine that targets the variant first spotted in South Africa, B.1.351. That variant appears to be able to evade immune responses triggered by earlier versions of the virus.

“The Phase 1 studies conducted by Moderna and NIAID … will produce immunogenicity data that will address this question,” John Mascola, director of NIAID’s Vaccine Research Center, told STAT in an email. “So data directly bearing on the question will be forthcoming over the next weeks and months.”

  • As Dr. Michael Roof pointed out:
    “Despite the rapid-fire perniciousness of this turbocharged viral beast that escaped the virology lab in Wuhan, I am still optimistic that using up-to-date knowledge, AI, and other computer applications will allow us at least a fighting chance… That said, our approach has to be open-minded and dynamic, realizing that this isn’t just any old virus coming out of nature’s realm.”

    Thank you for pointing out the nature of this virus. Dr. Redfield, an expert virologist and the former director of CDC, recently disclosed this in an interview with CNN’s Dr. Sanjay Gupta. Very intriguing if you watch the interview online.

  • Are we hiring children as writers here. Statnews seriously needs proofreading of its articles. This is not the first time. It is fine if the error does not confused the original meaning of the sentence. But the error was on a relevant sentence.

    “The spike proteins they trigger production of appear to hide the S2 region, he said.”

  • Statnews are very FOND of using the word experts, to the point that it misuse is so disguting. Most of people it labeled experts are junks.

    Example.

    1. Way back when Trump implemented the travel band, Statnews grab some random fresh graduate from public policy and labeled her as experts. She was complaining that travel ban was bad, I can’t remember all the nonsense she utter. WHO also complained of travel ban in that article. Guess want, most if not all countries in the world are now doing travel ban.

    2. Statnews has another article, that some “experts” are saying that the virus are mutating to be more contagious but not deadly. Unfortunately, brainless readers start believing that too. I had to response to that nonsense that since the UK variant had higher viral load, it damage more cells, as each virus enter the cell to replicate. Another brainless commenter disagree with me on that. Guess what, it had been proven that some variant are evolving to be more contagious and damaging if not deadly. In France, India, Brazil, younger people are in the ICU because of the variant. UK variant had been proven to be more contagious and damaging if not deadly.

    That is another great disservice done by Brix, making an a very optimistic assumptions on an unknown virus. Some people in their teens up to 30’s, are having brain fog and memory loss and becoming long covid. According to one scientist, the SAR2 spike can penetrate the brain blood barrier and can therefor infect the brain. He suspect this is the one causing the brain fog.

    Statnews, CAN YOU PLEASE STOP USING TO THE EXPERTS TO TRY TO LEND CREDIBILITY TO YOUR JUNK ARTICLE.

  • Despite the rapid-fire perniciousness of this turbocharged viral beast that escaped the virology lab in Wuhan, I am still optimistic that using up-to-date knowledge, AI, and other computer applications will allow us at least a fighting chance. This isn’t the 1950’s. That said, our approach has to be open-minded and dynamic, realizing that this isn’t just any old virus coming out of nature’s realm.

  • This is a very interesting and informative article, particularly for layman. I knew there was a phenomenon of imprinting but knew almost nothing about it.
    For the authors and scientists who were interviewed – MOST of us understand that speculating about possible turns the epidemic might take, to try to head it off and get us better treatment (I understand vaccines are not treatment in medical lingo, I mean in the larger sense of the word) is responsible medicine and needs to be done. Please do not take any criticisms about ‘Fear mongering” from a broken record playing that yet again, to heart. We are grateful for the information.

    This topic brings up the question – when the outbreak in Manaus, which would seem to have been a strong indication of the rise of a variant which escaped natural immunity to the first type, (and was, as it turned out) started sickening huge numbers of people – why did we not send our vaccines into Manaus in large numbers to see how well they worked against it? A few thousand doses each of Pfizer and Moderna vaccines would have been enough to know, by now, with certainty, how they will do against P1, right? I realize B1117 was the main variant threat back in December, but this appears to be a major lapse and it is still not clear it has been corrected.

  • More fear mongering from some of these scientists — really, it gets very old, very quickly.

    The spike’s S2 subunit is highly conserved and will almost certainly remain so as the virus mutates. And even it it does “hide” your immune system will very likely still kick in upon infection with some new strain. Remember, an infected unvaccinated person under 60 with no co-morbidities, likely had an effective immune response the current strain, and the variants will trigger the immune system again.

    And even for those outliers whose immune response is weak, due to the imprinting action, mTOR inhibitors like Rapamycin will modulate the infection. Therapeutics for some reason don’t get enough attention from STAT and others in the journalism community. Maybe because — Boo!!!– the “variants” are scarier?

    Look, we have to learn to live with this virus as it evolves, as we do the influenza viruses in general, and living in fear and altering “normal” life out of an irrational sense of caution has its own hazards.

    And we have to understand that older people with end of life inflammatory syndromes are in danger from ANY viral infection not just Covid. In contrast, the vast majority of people are robust enough to handle what gets thrown at them.

  • I wonder what the ramifications of imprinting are for:

    1. Which technology you originally used to get vaccinated (mRNA, adenovirus, protein sub-unit).
    2. What would be the most effective crossover (or not) to combat possible imprinting (mRNA to which one? adenovirus to which one? protein sub-unit to which one?)

  • So let me get this straight. Our natural immune system imprints it’s way to being more vulnerable to infection? Does this make any evolutionary sense to anyone?
    But, somehow, the vaccines do a better job than the natural immune system that took millennia do develop. It’s a wonder that the human race survived long enough for us to be around to develop these Incredible Vaccines. To me, this article sounds like a bunch of nonsense as well as being filled with speculation.

  • Excellent reporting! However, I’m still waiting for enough data to determine the effectiveness of the first round of vaccines let alone a second iteration.

  • Could imprinting be the reason why Covid doesn’t cause more serious infections in children? The thought before was the opposite that children are exposed to so many corona viruses during their childhood that they probably have already been exposed to a Covid like virus earlier. But perhaps the opposite is true. Young children may not have been imprinted with a virus similar to covid so their immune system is responding with a clean slate?????

    • Imprinting is not about the Covid infection, but about the way the immune system responds to an infection…where a previous in- fection would stimulate the bidy to produce more antibodies on the previous i fiction than against the new o fection.

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