Will ‘original antigenic sin’ undermine Omicron boosters? New research suggests ‘no’
Moderna and Pfizer-BioNTech are now racing to develop Omicron-specific boosters, hoping to be ready if the new immune-evasive variant becomes dominant globally. But it wasn’t always clear that variant boosters could even work.
After the first Covid-19 vaccines were authorized and talk began of variants and next-generation vaccines, several vaccinologists raised concerns in the media and the scientific press about a potentially deleterious phenomenon that sounds as if it were born out of the Vatican’s immunology wing: Original antigenic sin.
OAS — or, as less biblically inclined researchers like to call it, imprinting — was first discovered by researchers studying how older people respond to flu vaccines.
There are about 20 different flu viruses. Different strains are dominant in different years and each evolves quickly. So every fall, manufacturers try to include the right virus — and the right version of each of those viruses — in the annual shot, hoping to induce antibodies that match the virus people are most likely to encounter.
Researchers found, though, that regardless of the vaccine’s design, people produced the best and longest-lived antibodies against the flu strains they were first exposed to as kids. It was if, like baby ducks permanently mimicking the first duck or human they saw, our immune systems permanently molded around our first infection and got stuck there.
Researchers feared the same could happen with Covid-19 vaccines and infections. Although it’s relatively straightforward to design an mRNA vaccine that codes for a new spike protein, it wasn’t clear whether our immune systems would be nimble enough to adapt to the new instructions.
Injected with a variant-specific booster, maybe people would mostly just churn out copies of the antibodies they made after their first vaccination or infection. That would give the world far less latitude to respond to an immune-evasive variant like Omicron.
Data, though, have since come suggesting that’s unlikely to be a problem with this virus, encouraging vaccine developers that they can respond should the Omicron-specific boosters — or boosters for a future variant — be needed.
Rather than a fixed immune response to coronaviruses, researchers have observed a far more flexible, tunable one.
It’s “an important scientific question,” BioNTech CEO Uğur Şahin told reporters Wednesday. “And the data that we have observed — and again this is preliminary — is encouraging that the immune response can be fine tuned.”
Sahin and other researchers’ confidence come from test runs Moderna and BioNTech ran against other variants. Last winter, after the first variant that could partially evade antibodies from vaccines, Beta, arose in South Africa, Moderna designed a new vaccine construct and tested it in Phase I.
Although Beta ultimately vanished and Moderna abandoned the candidate, the Phase I study showed that people given the variant-specific booster produced high levels of Beta-specific antibodies.
“What we’ve seen suggests that antigenic imprinting … is not going to be a problem,” said John Mascola, head of the NIH’s vaccine research center. “I shouldn’t say it’s not going to be a problem, but it hasn’t been a problem so far.”
BioNTech has its own, less publicized studies on variant-specific boosters. In August, the German biotech launched a 1,245-person study to test four types of boosters: A booster of the original vaccine; an Alpha-specific booster; a Delta-specific booster; and a multi-valent booster that codes for both the Alpha spike protein and the Delta spike protein.
Unreleased data from those studies, Şahin said, have made the company confident they could also make a booster that combines multiple variants and confers broader protection, should that eventually be needed.
“One option, which I believe is not very likely, could be an Omicron-Delta variant,” he said.
Officials and executives are still tracking Omicron’s spread to see whether specific boosters will be needed. But if they are, it would be another case where the world has managed to avoid a potential immunological bullet from a virus that, for all the ways it’s surprised researchers, has proven “stupid easy” to vaccinate against.
Early in the pandemic, for instance, prominent immunologists and vaccinologists warned about the risk of antibody-dependent enhancement, in which the antibodies produced by vaccination or prior infection actually help the virus infect more cells. There was evidence that SARS could do this, but fortunately the vaccines ultimately proved to do quite the opposite in Covid-19, powerfully suppressing infection and disease.
Of course, no one is making any promises yet about Omicron boosters. Although the studies so far point away from original antigenic sin, they have been comparatively small and only covered a couple variants.
If Omicron boosters are needed, companies will need to run immunological studies on the new shots before they’ll be confident they work.
“The Phase I trial data, and NHP experiments, generally indicate that the variant-specific boosters are not (seriously) affected by OAS. It may be part of the picture, but there does still seem to be benefit,” John Moore, a vaccinologist at Weill Cornell, said in an email.” Whether that changes regarding Omicron? Slaughter a sheep and inspect the entrails … (Make sure you get animal study approvals first of course).”
