Some experts fear next-generation Covid vaccines could be worse

WWith Covid-19 vaccines, the world hopes to fight the virus that causes the disease. But some scientists are becoming increasingly concerned that due to a quirk in our own biology, future versions of vaccines may not always be as effective as they are today.

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

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


That footprint can be useful. In the 2009 H1N1 flu pandemic, older adults were protected by immune responses that they had 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 generate responses against the stresses that have evolved from the first time it was exposed.

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


Michael Worobey, who was involved in pioneering research on influenza imprinting, said he is concerned that responses to first-generation Covid-19 vaccines turn out to be “a high water mark” for people’s immune responses to these inoculations. .

“I think it’s something we need to think about,” Worobey, a professor of evolutionary biology at the University of Arizona, told STAT. “We could actually see lower efficacy five years from now, if people are still obsessed with remembering the answer the first time. [SARS-2] antigen they saw. “

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

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

However, not everyone in the conversation is convinced that there will be a problem.

Vineet Menachery is a coronavirus expert in the Medical Branch of the University of Texas at Galveston, one of the small communities of researchers who were studying coronaviruses before the Covid-19 pandemic. He pointed out that the SARS-2 spike protein, the protein that projects from the surface of the virus, giving it the appearance of wearing a crown, does not have as much leeway to change as the hemagglutinin proteins found on top of virus viruses. the flu.

Both the spike protein and hemagglutinin are the means by which their respective viruses adhere to the cells they are trying to infect; in the case of SARS-2 viruses, binding occurs through a receptor known as ACE2. But influenza viruses mutate at a much faster rate than coronaviruses and have much more room to change (mutational space, Menachery called it) without impeding their functionality.

“The changes we see in the [SARS-2] variants are not complete changes, “he said.

Imprinting is one of the reasons flu vaccines don’t protect as much as we’d like. The flu changes markedly and its constant changes allow influenza viruses to bypass the protections of the immune system generated by vaccination or previous infections. People who first encountered the H1N1 virus, for example, never receive as much protection from the H3N2 component of a flu vaccine as they do from the H1N1 component.

“Basically, I think of original antigenic sin as a kind of hierarchy in immune memory, meaning that you preferably reinforce what you’ve seen before, at the expense of developing responses to new things,” Cobey said. “It could affect the effectiveness of [Covid] vaccine in the future. “

Scott Hensley, sometimes a collaborator of Cobey, has seen some evidence of the coronavirus imprint in his research. Associate professor of microbiology at the University of Pennsylvania, Hensley and his colleagues were working to develop tests for Covid-19 antibodies in the early days of the pandemic. The work consisted of studying using blood samples from people who contracted Covid. They compared post-infection samples with blood drawn from the same individuals before the pandemic.

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

In other words, the Covid infection actually increased the immune system’s protection against a different virus, one that the immune system was already aware of.

Still, Hensley is not concerned with imprinting, or at least not among people who have been vaccinated with mRNA vaccines. The very strong immune response generated by the Moderna and Pfizer-BioNTech vaccines should negate any imprint impacts as SARS-2 mutates, he said. However, Hensley is concerned that people whose immunity to the virus comes from infection, not vaccination, may have a more difficult time managing variant viruses due to the effects of imprinting.

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

He noted that, in the early stages of SARS-2 infection, the immune system generates a response to a portion of the spike protein called S2. Later, the immune system turns its attention to other parts of the spike, particularly the part of the protein that binds the virus to the cells it invades, known as the receptor-binding domain.

It is not yet known whether the early focus on S2, which does not change much from virus to virus, will blind the immune system to changes in other parts of the spike protein – changes that updated vaccines would attempt to teach the immune system to respond. . a, Topham said.

Topham does not believe this is a problem for vaccinated people, due to the way the vaccines in use have been designed. The spike proteins that trigger production appear to hide the S2 region, he said. The immune system cannot fixate on something it cannot see.

For people whose immunity comes from an infection, Topham sees three possible scenarios. “It can be a problem, because S2-specific immune cells outperform immune cells against other components of the spike protein that you really need to get protection. It may be inconsequential as 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 boosts the immune system more quickly. “

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

“In fact, it could end up with a broader immune response,” 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 conducted by scientists from the Finnish Institute of Health and Welfare and the University of Turku on vaccination against H5N1 bird flu. The H5N1 vaccine that does not contain adjuvants (enhancing compounds) appears to generate poor immune responses. But in an article published in the journal Vaccine, the researchers reported that a prime-and-boost regimen using two different H5N1 vaccines, made from different strains of the virus, induced a strong and long-lasting response.

We may find out if this is going to be a problem sooner than you think. Moderna is working with the National Institute of Allergies and Infectious Diseases, which helped him design his original Covid vaccine, to test an updated version of his vaccine that targets the variant first detected in South Africa, B.1.351. This variant appears to be able to evade the 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 the NIAID Vaccine Research Center, told STAT in an email. “Therefore, the data directly related to the question will be published in the coming weeks and months.”

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