[Question] What fraction of breakthrough COVID cases are attributable to low antibody count?

[johnswentworth]

To what extent are COVID cases in vaccinated people a result of low antibody count, vs other factors (e.g. initial viral load)? Where does most of the variance come from?

Motivation for this question: in a world where most breakthrough COVID cases hit people with low antibody count, one could get some kind of antibody test (probably of a particular type) and then either (a) get an extra vaccine if antibodies are low, or (b) just don’t worry if antibody counts are high. That makes antibody tests (of whatever the particular type is) very high value, since we can behave very differently in those two cases. In a world where most of the variance comes from other factors (like initial viral load), results of an antibody test don’t provide so much value.

Related: Is antibody testing to assess effects of vaccines on you a good idea?

[jacopo]

According to my understanding (which comes from popularized sources, not I am not a doctor nor a biologist) antibody counts are not the main drivers of long-term immunity. Lasting immunity is given by memory T and B cells, which are able to quickly escalate the immune response in case of new infection, including producing new antibodies. So while high antibody count means you’re well protected, a low count some months after the vaccine could mean that the protection has reduced, but in almost all cases you will be protected for a much longer time. Note that low antibody count immediately after the vaccine would be different, but I don’t know if this even happens in people with an healthy immune system. Unfortunately there is no easy way to test how many memory T/​B cells you have against a specific virus, without even going into how responsive they are.

So I think testing for antibodies before giving third doses would still result in giving the booster it to many more people than need it. Depending on how many doses you save, and on the costs of testing vs vaccinating, it may still be worth it. But it’s probably more practical at this time to give the booster to the people we expect have developed less memory cells, in other words the immunocompromised and maybe elderly people. For the others, I would simply wait to have more data, and ship the extra doses to poor countries.

[DirectedEvolution]

The strategy you’re proposing is that (provided antibodies are major controllers of infection), everybody gets routine antibody tests, then use the results to decide if we get a vaccine booster shot.

An alternative is to give everybody vaccine booster shots on a schedule, with no pretest.

Which strategy should we use should depend on a cost/​benefit analysis of each approach. Here are some factors that might be relevant.

• Cost. If antibody tests cost more than administering a vaccine booster, then using them as a pre-test would be costlier than skipping them. If they’re cheaper, then it depends on both the test vs booster cost differential and the proportion of patients who’d require a booster.

• Time. Let’s assume it takes the same amount of time for each patient to get an antibody test and a booster shot. If so, antibody tests double the time commitment for everybody who gets a vaccine shot, while saving no time for those who ultimately get no shot. Conceivably, antibody tests could be self-administered, as when diabetics check their blood sugar levels (though you’d test for antibodies much less frequently).

• Discomfort. Antibody tests involve a finger prick; vaccines involve a shot. The antibody test might allow people to avoid getting a shot, but would mean that all those who ultimately do get a booster have to get poked twice in a few days. We can probably more or less ignore vaccine hesitancy as a factor in discomfort, since they’re not even getting their first shot.

• Safety. The second vaccine shot seemed to produce more side effects than the first shot. Would this pattern continue under a regime of periodic boosters? If so, antibody tests might be very helpful for allowing people to avoid these side effects. About 25% of people experience systemic side effects.

• Efficacy. As further strains emerge, we might find that boosters are required not because antibody levels have fallen, but because they have become less effective at fighting the most prevalent strain of covid. Since we’ll need to study the efficacy of the vaccine against new strains of covid, the same way we do for flu, it seems like we ought to be able to fold in antibody tests to the same study.

In the long run, both of these strategies are based on the assumption that we’ll fail to adequately vaccinate the planet and eliminate covid the way we eliminated smallpox.

I think the strongest point in favor of thoroughly exploring the antibody test-based approach is avoidance of side effects.

Let’s say that getting an antibody test would take 45 minutes out of your day on average. For a population of 1,000 people, that’s 750 person-hours. Let’s define “serious side effects” of covid as being out of commission for one waking day (16 hours). 750 person-hours is about 47 waking days. So you’d need to spare 5% of the population the experience of “serious side effects” as I’ve defined them to make antibody tests worthwhile exclusively on time savings; less if you include the discomfort of what some have described as “the worst hangover” or being “hit by a truck,” or the economic losses from people missing work. This means that if about one in five of the 25% subgroup who report systemic side effects are taken “out of commission,” and if antibody tests were a perfect determinant of need for a booster, then it would be worthwhile to use them to avoid giving unnecessary vaccine. That’s probably an upper bound.

I think the main argument against the antibody test approach is the time budgets of individual people. It seems really likely to me that if people invest the time to get an antibody pre-screening test, many who need a booster will neglect to go back for the second visit. Paying people to get the test and booster shot (if necessary) would most likely counteract this problem. But I’d hesitate to support the antibody prescreening concept unless we were paying people to get vaccinated, as well as making it mandatory (as we should be anyway).

[AdamGleave]

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).

[DirectedEvolution]

From the article:

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.

[AdamGleave]

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):

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.

[DirectedEvolution]

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.

[johnswentworth]

Great analysis, though it’s narrower than what I originally had in mind. The question didn’t really nail down one use-case, so here’s a few other possibilities:

• One advantage of the testing approach is that, if antibody counts are high, it potentially offers very high confidence in immunity. Whereas when taking vaccines blindly, one needs potentially quite a few to attain high certainty (especially since people who have low antibody counts after the first couple are more likely to have something going on which messes up later doses too). So, if someone is really paranoid and wants high certainty, the test approach is potentially cheaper.

• Similarly, if one wants to orchestrate a large group of people being together, then very high confidence in immunity is potentially valuable.

• On a personal level, if government restrictions prevent multiple boosters, a test could be useful for deciding what level of precautions to take.

Mostly I’m thinking about this as an individual/​private group strategy, not as a whole-population thing. Though even at the whole-population level, I do think there would be a lot of value in being able to say “do X, and once the test passes you can completely stop all these annoying precautions without having any significant chance of catching COVID”. (As opposed to what we have now, where a lot of vaccine hesitancy comes from “but I can still catch COVID even with the vaccine”.)

[DirectedEvolution]

There are probably some private meetings that would benefit from the antibody testing strategy. As you point out, personalized knowledge of the strength of your immunity would enable more precise risk analysis when planning get-togethers and outings in circumstances involving a lot of strangers.

Meetings in which all participants are known, and there is some level of trust or ability to enforce rules, might benefit more from rapid testing for Covid, rather than testing for antibodies. Of course, you could do both for the strongest level of confidence. But we have rapid tests available right now. It seems plausible that some combination of rapid tests, or PCR tests followed by rapid tests for large or high-stakes meetings, could provide enough security that further investments in safety would be best focused on circumstances where you have less control.

So it seems like antibody tests potentially permit more low-trust interactions, while infection tests permit more high-trust interactions. If antibody tests are known to be strong predictors of immunity, we can take them and decide whether to go to a music festival. If we’re all trustworthy friends and all get tested daily for Covid, we can create our own mass Covid bubble and hold a big wedding.

I’m quite pessimistic about the likelihood that a meaningful amount of vaccine hesitancy is due to the perception that the vaccine’s efficacy is too low to be worth bothering. There’s just a collection of justifications floating around the antivax population, and they utter whichever one they’ve seen work to shut people up in the past.

But insofar as this perception is playing a role, identifying people whose vaccines “didn’t take” and giving them targeted boosters might help. You could tell a story that we’re trying to give people as little vaccine as possible—just to the people who we are confident really need it. Antibody tests might be a helpful supplement here. Some vaccine hesitant people might suspect they’ve already had Covid, in which case they might think there’s less of a point in getting vaccinated (and as far as I know, they might be right?). If we can distinguish those who have no or low antibodies from those who have a higher level, perhaps this would sometimes create traction to motivate those with little-no resistance to get the jab. Then again, maybe they’d use greater evidence for fading immunity as a reason not to get vaccinated at all.

From this paper, young children have durably high antibody levels, while older children and adults have low or transient antibody levels. It suggests that the antibody transience in adults may be due to original antigenic sin, since we’ve had a lot more colds than children and may have already fine-tuned our immune systems to deal with those viruses, making them less able to adapt to handle Covid. This paper isn’t the empirical study you’d really want, but it seems to support the idea that antibody level does control immunity to Covid, that antibody tests would be a useful way to check your immunity, and that adults really do need to worry about their immunity fading within months of getting vaccinated.

One of my remaining concerns with antibody tests is that they would need to be chosen to test against all strains of the virus. You don’t want an antibody test that works against an early strain, but not against the most prevalent one. Right now, I have a BINAXnow rapid test in my closet, and it may well sit there for months unused until it expires. It wouldn’t surprise me at all if a lot of people did the same thing with some sort of home antibody test kit, but instead of throwing it out at expiration (or after a shift in viral population), they used it anyway, and gained a false sense of security. So I’d probably want antibody tests to be administered by a medical professional, rather than in a home test.

[cistrane]

If antibodies are low, that might be weak evidence that you are resistant/​immune to the vaccine itself.

mRNA vaccine use PEG in their lipid nanoparticle formulations, if you somehow got antibodies against PEG, you’d be immune to the vaccine, it would not work for you ne matter how many booster you took.

[CraigMichael]

This seems reasonable to me at a high level (not including relative costs of tests vs. vaccines, assuming we can reliably enough test, and that and likelihood of having waning antibodies would vary enough individually that this would make sense).

I’m not sure how one would know what to attribute breakthrough cases to with being in some kind of laboratory environment where viral dose was measured and antibodies were measured and we saw who did and didn’t get sick… I’m not a medical professional so maybe there’s things I’m missing here.

[johnswentworth]

Yeah, I’m not really imagining a lab test on the matter. It seems like the sort of thing where someone with the right dataset could do some clever math and back out a reasonable estimate.