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.


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.


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.”


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