As #omicron-specific boosters near, scientists debate how ‘original antigenic sin’ will influence immune responses.
In the beginning, when the coronavirus was new, the quest for a #COVID19 vaccine was simple. Everyone started out susceptible to the virus. Shots brought spectacular protection. But the next chapters of life with the virus — and the choice of booster shots for the fall and beyond — will be complicated by the layers of immunity that now ripple through the population, laid down by past infections and vaccinations.
When it comes to viral infections, past is prologue: The version of a virus to which we’re first exposed can dictate how we respond to later variants and, maybe, 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 prompts a constellation of questions. Are our immune systems stuck still revving up defenses against a version of the virus that has vanished? Will updated booster shots that are designed to thwart variants be much better than the original vaccine? How often will we be reinfected? Is there a better way to broaden immunity?
The answers to those questions will influence our long-term relationship with the coronavirus — and the health of millions of people. But more than two years into the pandemic, the quest to unravel these riddles underscores the seemingly unending complexity of the battle against a new pathogen.
When the virus emerged, no one had encountered SARS-CoV-2 before, so our immune systems started in pretty much the same vulnerable spot — what scientists call “naive.”
Now, people have been infected, vaccinated, boosted, reinfected and boosted again — in varying combinations. People’s immune systems are on slightly different learning curves, depending on when they were infected or vaccinated, and with what variants or vaccines.
“There are no cookie-cutter answers here,” said John P. Moore, a professor of microbiology and immunology at Weill Cornell Medicine. “An omicron infection after vaccination doesn’t mean you’re not going to get another one a bit further down the road. How long is a bit further down the road?”Scientists are watching in real time as original antigenic sin plays out against the coronavirus — and debating how it will influence future vaccine strategy. Contrary to its biblical thunderclap of a 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 revamped fall boosters have limited benefits, because people’s immune memories are dominated by their first experience with the virus.
“We may have gotten about as much advantage out of the vaccine, at this point, as we can get,” said Barney Graham, an architect of coronavirus vaccines who now focuses on global health equity at Morehouse School of Medicine in Atlanta. Graham emphasizes that the vaccines are doing exactly what they were designed to do: keep people out of the hospital. Retuning them will have benefits, albeit limited.
“We can tweak it and maybe evolve it to match circulating strains a little better,” Graham said. “It will have a very small, incremental effect.”
Echoes of immunity
More than 60 years ago, a virologist named Thomas Francis Jr., observed that influenza infections in childhood had lifelong repercussions. For decades after, people’s immune systems carry an imprint from their first flu, activating defenses primarily against the original version of the virus they encountered. He called it “the doctrine of original antigenic sin.”
The same thing is happening 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 on standby, created by previous vaccinations or infections.
“People are now walking around with different immune-imprinted covid responses, depending on what vaccine schedules they’ve had — one, two or three doses — and what infections they have had in the past,” said Rosemary Boyton, a professor of immunology and respiratory medicine at Imperial College London. “Imprinting is different according to where you live in the world, what vaccines you received — and that’s determining the subsequent immune response.”
In flu, the immunological echoes of original antigenic sin have real consequences: When flu strains are similar to the ones encountered in childhood, people are better protected against severe 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 people who were exposed to H1N1 in childhood had stronger immune responses than younger people who had been infected with other strains. When a flu strain is a more distant relative of that initial exposure, people may be more susceptible.
There’s not a consensus on how original antigenic sin plays out with the coronavirus — and it’s a touchy subject among immunologists. Many quarrel about whether “sin” is the appropriate word for a phenomenon that undergirds our immune system’s ability to provide partial protection against changing viruses.
But time is of the essence: Companies are already manufacturing fall boosters based on a new recipe. Many scientists think that, in the absence of certainty, moving forward with retuned boosters is the best strategy — even if they may offer short-term protection, mostly against severe illness.
“Maybe 10 to 15 years from now, we live in a world where the vaccine is birth-year specific or make 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 science fiction frontier here, of figuring out these imprinting questions.”
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