As omicron-specific boosters approach, scientists discuss how ‘original antigenic sin’ will affect immune responses
August 23, 2022 at 6:00 am EDT
(Melanie Lee for The Washington Post) Comment on this story
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In the beginning, when the coronavirus was new, the search for a vaccine was simple. Everyone started out vulnerable to the virus. The shots brought spectacular protection.
But the next chapters of living with the virus — and choosing booster shots for the fall and beyond — will be complicated by the layers of immunity now rippling through the population, built up from previous infections and vaccinations.
When it comes to viral infections, past is prologue: The version of a virus we’re first exposed to can dictate how we respond to later variants and, perhaps, how well vaccines work.
It’s a phenomenon known by the forbidding name of original antigenic sin and, in the case of the coronavirus, it raises a constellation of questions. Is our immune system stuck reviving defenses against an extinct version of the virus? Reinforcement shots that are will be updated is it designed to prevent variants from being much better than the original vaccine? How often will we be reinfected? Is there a better way to boost immunity?
The answers to these questions will affect our long-term relationship with the coronavirus — and the health of millions of people. But more than two years after the pandemic, the quest to unravel these puzzles underscores the seemingly endless complexity of the battle against a new pathogen.
When the virus appeared, no one had faced SARS-CoV-2 before, so our immune systems started from almost the same vulnerable point – what scientists call “naive”.
Now, people have been infected, inoculated, enhanced, reinfected, and regenerated again — in various combinations. People’s immune systems are on slightly different learning curves depending on when they were infected or vaccinated and with which strains or vaccines.
“There are no cookie-cutter answers here,” said John P. Moore, professor of microbiology and immunology at Weill Cornell Medicine. “One microbe infection after vaccination doesn’t mean you won’t get another one down the road. How long is it just down the road?’
Scientists are watching in real time as the original antigenic sin plays out against the coronavirus – and are debating how it will affect future vaccine strategy. Unlike the biblical lightning of the name, the phenomenon is nuanced – more often beneficial or neutral than harmful.
It helps explain why vaccines based on the original virus continue to keep people out of the hospital, despite challenging new variants. But it may also mean that renewed autumn boosters have limited benefits because people’s immune memories are dominated by their first experience with the virus.
“We may have gotten as much benefit out of the vaccine, at this point, as we can,” said Barney Graham, a coronavirus vaccine architect who now focuses on global health equity at the Morehouse School of Medicine in Atlanta. Graham stresses that vaccines do exactly what they were designed to do: keep people out of the hospital. Reuniting them will have benefits, albeit limited.
“We can tweak it and maybe evolve it to match the current strains a little better,” Graham said. “It will have a very small, incremental effect.”
More than 60 years ago, a virologist named Thomas Francis Jr. observed that influenza infections in childhood had lifelong effects. For decades afterward, people’s immune systems carry an imprint of their first flu, activating defenses primarily against the original version of the virus they encountered. He called it “the doctrine of original sin.”
The same thing happens with the coronavirus. A growing number of studies show that when the omicron variant infects, it causes the immune system to rapidly activate immune memory cells that are already in standby, created by previous vaccinations or infections.
“People are now walking around with different immune responses to the coronavirus, depending on which vaccine schedules they’ve had – one, two or three doses – and what infections they’ve had in the past,” said Rosemary Boyton, professor of immunology. and respiratory medicine at Imperial College London. “The imprinting is different depending on where you live in the world, the vaccines you’ve received — and that determines the subsequent immune response.”
In influenza, the immunological echoes of original antigenic sin have real consequences: When flu strains are similar to those encountered in childhood, people are better protected against serious illness. The 1918 flu pandemic was caused by an H1N1 strain, which continued to circulate for decades afterward. When the 2009 H1N1 pandemic occurred, older adults who had been exposed to H1N1 in childhood had stronger immune responses than younger adults who had been infected with other strains. When a flu strain is more distantly related to that initial exposure, people may be more susceptible.
There’s no consensus on how original antigenic sin plays into the coronavirus — and it’s a touchy subject among immunologists. Many debate whether “sin” is the right word for a phenomenon that highlights our immune system’s ability to provide partial protection against changing viruses.
But time is of the essence: Companies are already making fall boosters based on a new recipe. Many scientists believe that, in the absence of certainty, promotion with retuned enhancers is the best strategy — even if they may offer short-term protection, especially against serious diseases.
“Maybe 10 to 15 years from now, we’re living in a world where the vaccine is year-of-birth specific, or we’re making strain selection decisions that take into account different immune histories in the population,” said Katelyn Gostic, a researcher at the University of Chicago. . “I think we need and are actively developing better technologies and better techniques to try to work at the frontier of science fiction here, to find these questions that capture.”
How the immune system learns
to identify a virus
After a virus invades, dendritic cells grab pieces of the virus.
The dendritic cells then seek helper T cells that match characteristics of the viral fragments.
Once paired, an activated assistant
The T cell then locates
B cells that also match the distinct characteristics of the virus.
Activated B cells turn into plasma cells that produce antibodies that block the virus to fight the infection. Some become memories
B cells.
Antibodies flood the body and attach to the virus to prevent it from infecting more cells.
Memory B cells remain in the body after the first infection is cleared. They can then quickly reactivate to produce more antibodies if the same virus is encountered again.
How the immune system learns
to identify a virus
After a virus invades, dendritic cells grab pieces of the virus.
The dendritic cells then seek helper T cells that match characteristics of the viral fragments.
Once paired, an activated assistant
The T cell then locates B cells that also match the distinct characteristics of the virus.
Activated B cells turn into plasma cells that produce antibodies that block the virus to fight the infection. Some become memory B cells.
Antibodies flood the body and attach to the virus to prevent it from infecting more cells.
Memory B cells remain in the body after the first infection is cleared. They can then quickly reactivate to produce more antibodies if the same virus is encountered again.
How the immune system learns to recognize a virus
After a virus invades, dendritic cells grab pieces of the virus.
The dendritic cells then seek helper T cells that match characteristics of the viral fragments.
Memory B cells remain in the body after the first infection is cleared. They can then quickly reactivate to produce more antibodies if the same virus is encountered again.
Once paired, an activated assistant
The T cell then locates B cells that also match the distinct characteristics of the virus.
Activated B cells turn into plasma cells that produce antibodies that block the virus to fight the infection. Some become memory B cells.
Antibodies flood the body and attach to the virus to prevent it from infecting more cells.
How the immune system learns to recognize a virus
Activated B cells turn into plasma cells that produce antibodies that block the virus to fight the infection. Some become memory B cells.
Antibodies flood the body and attach to the virus to prevent it from infecting more cells.
After a virus invades, dendritic cells grab pieces of the virus.
The dendritic cells then look for a helper
T cells that match characteristics of viral fragments.
Once a match is made, an activated helper T cell then locates B cells that also match the distinct characteristics of the virus.
Antibodies attached
to the virus
Memory B cells remain in the body after the first infection is cleared. They can then quickly reactivate to produce more antibodies if the same virus is encountered again.
How the immune system learns to recognize a virus
After a virus invades, dendritic cells grab pieces of the virus.
The dendritic cells then seek helper T cells that match characteristics of the viral fragments.
Memory B cells remain in the body after the first infection is cleared. They can then be quickly reactivated
to produce more antibodies if the same virus is encountered again.
Once paired, an activated assistant
The T cell then detects the B…
