I largely with this analysis. One major possible “side-effect” of a third booster is original antigenic sin. Effectively, the immune system may become imprinted on the ancestral variant of the spike protein, preventing adaptation to new variants (whether via direct exposure or via future boosters targeting new variants). This would be the main way I could see a third booster being seriously net-negative, although I don’t have a good sense of the probability. Still, if antibody levels are low, the benefit of a booster is greater and I’d guess (caveat: not an immunologist) the risk of antigenic imprinting is somewhat lower (on the basis that the immune response has already decayed).
Original antigenic sin, also known as antigenic imprinting or the Hoskins effect, refers to the propensity of the body’s immune system to preferentially utilize immunological memory based on a previous infection when a second slightly different version of that foreign pathogen (e.g. a virus or bacterium) is encountered. This leaves the immune system “trapped” by the first response it has made to each antigen, and unable to mount potentially more effective responses during subsequent infections.
This was the first time I’ve encountered this concept. It actually made it seem like a booster shot would just be ineffective, rather than “seriously net-negative.” Immunological memory would be optimized for the early variant the vaccine was designed for, and would be unable (or less able?) to update for the new variant.
Pfizer and Moderna vaccines target the spike protein. However, there are several other potential protein targets. Maybe the booster could be designed to target these instead.
That said, my read on the original antigenic sin article makes it seem like a plausible cause of breakthrough cases of Covid. If so, then I’d predict that antibody levels wouldn’t be a good predictor of susceptibility to infection. But it would be much better to base this on empirical data, and I don’t know if that exists.
It could be net-negative if receiving a booster shot caused stronger imprinting, making future immune response less adaptive. I don’t have a good sense of whether this original antigenic sin effect has already saturated after receiving two-doses (or even a single-dose), or whether it continues to become stronger.
As suggested by a recent observation in naturally immunized individuals receiving two doses of the Pfizer COVID-19 (Comirnaty) vaccine, original antigenic sin may pose a problem in future research and development of vaccines.16 While the first dose of the vaccine was able to raise the preexisting levels of functional and specific antibodies, these either failed to change or even declined after the second dose (virus-neutralizing antibodies), and the same applied to the levels of antigen-specific antibody-secreting cells. As this observation was made in only a small group of 13 subjects with naturally acquired immunity against SARS-CoV-2, who had rather average or below-average levels of the antibodies assessed, one may expect an enhanced effect of original antigenic sin after new vaccination against COVID-19 in those with manyfold higher antibody levels after complete immunization.
That said, I’d expect a third booster to be protective against Delta, given that vaccines against ancestral variant are still highly effective against Delta and that Delta is a significant threat right now. But I do think it’s plausible (though not firmly established) that a third booster shot may reduce the effectiveness of future variant-specific boosters. Targeting dramatically different protein targets might well help, although might also take longer to get approved.
Ultimately, I expect a third booster will still make sense for a lot of people, if (a) your immune response has waned (e.g. 6 months or longer since 2nd dose, or immunocompromised); and (b) you expect to be receiving significant exposure from Delta in the immediate future.
One possible strategy in a world of sane and effective governance might be to reserve one or more protein targets for a truly global mass-vaccination campaign. Really drill in the idea that we have to wipe out Covid or else live in a world that’s long-term deadlier than it was before. Produce enough vaccine and infrastructure to get the planet vaccinated in a short period of time. Then deliver it all at once. This could be going on in the background while we maintain our present efforts, building consensus and establishing infrastructure.
I largely with this analysis. One major possible “side-effect” of a third booster is original antigenic sin. Effectively, the immune system may become imprinted on the ancestral variant of the spike protein, preventing adaptation to new variants (whether via direct exposure or via future boosters targeting new variants). This would be the main way I could see a third booster being seriously net-negative, although I don’t have a good sense of the probability. Still, if antibody levels are low, the benefit of a booster is greater and I’d guess (caveat: not an immunologist) the risk of antigenic imprinting is somewhat lower (on the basis that the immune response has already decayed).
From the article:
This was the first time I’ve encountered this concept. It actually made it seem like a booster shot would just be ineffective, rather than “seriously net-negative.” Immunological memory would be optimized for the early variant the vaccine was designed for, and would be unable (or less able?) to update for the new variant.
Pfizer and Moderna vaccines target the spike protein. However, there are several other potential protein targets. Maybe the booster could be designed to target these instead.
That said, my read on the original antigenic sin article makes it seem like a plausible cause of breakthrough cases of Covid. If so, then I’d predict that antibody levels wouldn’t be a good predictor of susceptibility to infection. But it would be much better to base this on empirical data, and I don’t know if that exists.
It could be net-negative if receiving a booster shot caused stronger imprinting, making future immune response less adaptive. I don’t have a good sense of whether this original antigenic sin effect has already saturated after receiving two-doses (or even a single-dose), or whether it continues to become stronger.
My sense is this is an open question. From Petras et al (2021):
That said, I’d expect a third booster to be protective against Delta, given that vaccines against ancestral variant are still highly effective against Delta and that Delta is a significant threat right now. But I do think it’s plausible (though not firmly established) that a third booster shot may reduce the effectiveness of future variant-specific boosters. Targeting dramatically different protein targets might well help, although might also take longer to get approved.
Ultimately, I expect a third booster will still make sense for a lot of people, if (a) your immune response has waned (e.g. 6 months or longer since 2nd dose, or immunocompromised); and (b) you expect to be receiving significant exposure from Delta in the immediate future.
One possible strategy in a world of sane and effective governance might be to reserve one or more protein targets for a truly global mass-vaccination campaign. Really drill in the idea that we have to wipe out Covid or else live in a world that’s long-term deadlier than it was before. Produce enough vaccine and infrastructure to get the planet vaccinated in a short period of time. Then deliver it all at once. This could be going on in the background while we maintain our present efforts, building consensus and establishing infrastructure.