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T cells recognize recent SARS-CoV-2 variants (nih.gov)
109 points by onetimemanytime on March 31, 2021 | hide | past | favorite | 33 comments

Another recent study [1], discussed on This Week in Virology [2], also found T-cell immunity to be robust against mutations. However, there seems to be an open question of how well natural T cells, trained on the whole virus, will compare to T cells trained on vaccines that only have the spike protein or some other subset.

[1]: https://www.biorxiv.org/content/10.1101/2021.02.27.433180v1 [2]: https://www.microbe.tv/twiv/twiv-736/

I recall reading that the enhanced immune response from the vaccines were more protective than a natural infection.

Why is this post downvoted?

I know that P.1 (Brazil variant) seems to totally avoid natural immunity. The proof is from the city of Manaus, which was over 75% infected in October 2020. A resurgent wave of COVID19 hit in January 2021.

At first, this didn't seem possible. But upon further study, it seemed that P.1 was avoiding natural immunity. So its reinfecting a ton of people in Manaus.


In contrast, the Pfizer vaccine has shown to confer immunity to both the original strain AND to P.1. As such, the immune response created from Pfizer absolutely offers better protection, once we account for the variants (especially P.1 and B.1.351, which both have defenses against natural immunity)

B.1.351 is the other "immune avoiding" variant. And I await for more studies before making a conclusion on that matter.


EDIT: It seems like the article is discussing B.1.351 among its list of variants. That's good: the South African strain seemed like it had some ability to avoid our immune system, but our T-cells are still functioning against it. So a P.1 / Manaus event probably won't happen.

>The proof is from the city of Manaus,

The Manaus data was not very compelling. Lots of selection bias in their sampling.

There's multiple studies and multiple sets of data from Manaus. You'll have to be more specific. Which data, from which study, is untrustworthy?

I do not have the citation handy, but in one study, they recruited individuals by enticing them with the results; e.g. if you take take part in the study, we will give you the antibody result. This would obviously bias the results toward people that believed they had the virus, but didn't have a test when sick.

OP is likely talking about: https://science.sciencemag.org/content/371/6526/288?ijkey=01...

Which was originally reported in the popular press as "herd immunity doesn't real". The methodology seems weak to me, both in terms of sampling and how poorly some of the adjustments in the attack rate/seropositivity estimates were justified.

This paper, Buss et al 2021, was cited wrt 67% attack rate and 75%+ seroprevalence in Faria et al 2021: https://www.biorxiv.org/content/10.1101/2021.03.12.435194v2

This in turn was cited in eg Dejnirattisai et al 2021, as if it were the original source of the seroprevalence claims/data: https://www.biorxiv.org/content/10.1101/2021.03.12.435194v2 Note the lack of a citation for Buss et al 2021.

The error bars in Buss et al 2021 are awfully narrow given how uncertain many of the assumptions made were in correcting the seroprevalence estimates. Further, the idea that P1 seems to "totally avoid natural immunity" (in comparison to vaccine immunity) is not borne out by the experimental data (eg Dejnirattisai et al 2021, linked above, or Tarke et al 2021: https://www.biorxiv.org/content/10.1101/2021.02.27.433180v1). Both convalescent and vaccine sera showed reduced neutralization rates for P1; you see similar behavior in other potent VOCs like B1.1.7 (Dejnirattisai et al 2021 bis: https://www.cell.com/cell/fulltext/S0092-8674(21)00222-1) and B1.351 (Zhou et al 2021: https://www.researchgate.net/publication/349058926_Reduced_N...). And given the lack of transparency in any of these papers regarding how the antibodies sourced from convalescent sera were chosen for use, it's hard to say for certain that there isn't yet another selection issue here.

> There's multiple studies and multiple sets of data from Manaus.

If you are aware of another data set from Manaus from the period prior to P1 emergence which used a different methodology to claim 75%+ seroprevalence, I'd love to take a look at it. Otherwise, it seems like all the claims are ultimately sourced from the estimates of Buss et al 2021.

> I know that P.1 (Brazil variant) seems to totally avoid natural immunity.

This is completely false, and is a poor extrapolation from a faulty initial data point. There have now been several publications -- including the J&J clinical trial data itself [1] -- which show that immune responses induced by non-variant virus (or vaccine) are protective against the Brazilian variant.

There is some evidence that a particular mutation in the spike protein of the Brazilian variant can partially evade neutralization by particular antibodies, but this is far from "totally avoiding natural immunity".

> The proof is from the city of Manaus, which was over 75% infected in October 2020.

This number is based on a study that was written in summer 2020 [2], and used a number of questionable "adjustments" to the raw seroprevalence data to arrive at their conclusion. Raw seroprevalence data (Figure 2) was closer to 30%, not 75%.

The parsimonious conclusion is that the paper citing 75% seroprevalence in Manaus was wrong. Science really should retract this paper, or publish an addendum. It's an example where low-quality science is leading to a lot of unnecessary panic and speculation.

[1] https://www.ucsf.edu/news/2021/03/420071/how-effective-johns...

[2] https://science.sciencemag.org/content/371/6526/288

Use of blood donors is itself questionable and open to selection bias. Particularly if blood donors were getting free antibody testing and seeing the results, but even if they weren't. The authors seem to only have considered the demographics of the sample selection, and somewhat poorly.

Oh, definitely. I don't dispute the need for the adjustments that the authors were applying. It's just that...after a certain amount of "adjustment", what good is your prediction, anyway? Correcting the seroprevalence by a few percent is one thing. "Correcting" it by over 200% is quite another.

Basically, folks are going back to this paper (or more realistically: not reading it at all, and simply parroting headlines), ignoring the intense massaging of the data, and claiming that reality disagrees with the predictions from the paper, therefore reality must be wrong.

Right, I would argue there's factors that might call for a 200% correction the other direction. You just can't validate their tea leaf reading here of what are the correct set of corrections.

You say totally false, but your own favored hand-on-the-scale (which could be reasonable) adjustment leaves it at NOT in any way totally false

There is no adjustment. Those are the raw values.

You make it sound as if immune evasion is a binary thing. It's a spectrum. We don't need to worry about 100% evasion suddenly appearing and it's definitely not what we are seeing with B.1.351 and P.1. There are somewhat lower antibody titers with current vaccines, but they are still very effective both in antibody and T-Cell response it seems.

"Proof" from Manaus would have to be replicated in lab settings and all the data from lab tests show that there is some slight immune escape for P.1, but by no means is it total.

Same here, but that's adaptive immune response with antibodies. T-cell response is a different matter, and we're just beginning to learn how it works with COVID.

Sounds like good news.

There's also this bit at the end:

> Optimal immunity to SARS-Cov-2 likely requires strong multivalent T-cell responses in addition to neutralizing antibodies and other responses to protect against current SARS-CoV-2 strains and emerging variants, the authors indicate. They stress the importance of monitoring the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine if booster vaccinations are needed.

I haven't heard a lot of discussion around that, but it seems pretty logical to me that we'll continue to see substantial numbers of new variants for this virus, and thus there's a good chance we'll eventually need booster vaccinations to maintain immunity, unless (until?) we could get the whole planet vaccinated and eradicate the disease.

But since eradication seems highly unlikely, I'm hoping that we'll find the basic vaccines we've come up with so far can be modified to target new variants much in the way we come up with a new flu shot every year and don't have to go through the same full approval and manufacturing ramp-up process.

Eradication would have been the economically most sensible approach, but that was also true for elimination within the countries that would be paying for it - and it's not what they chose. Some of them apparently figured if you kill half a million of your people and "open up" your economy you can... offset the enormous cost of losing all those people by pretending they aren't dead? I honestly don't know, I suspect it'll turn out that nobody actually did any analysis, they just assumed if they can spout a talking point and have the numbers to push through the policy Mother Nature will have to go along with them, and er, nope.

So I don't expect them to pursue eradication either once the immediate local threat from the pandemic recedes. There's no great commitment to eradication generally from these countries, the funding mostly comes from charitable donation, even though obviously disease eradication makes economic sense as an investment. How much money for example, did your government spend on global elimination efforts for Rinderpest? Or did it just say "Not our problem" the moment there was no disease in their own cattle?

I'm not seeing any evidence that eradication of a virus like this would have been at all likely, even with extreme measures.

If the virus has a viable non-human reservoir then eradication becomes very difficult and in some cases impossible. We likely cannot get rid of Influenza because viruses from that family thrive in a huge number of other mammals. So you'd be chasing it down in pigs, and in chickens, and it becomes an insurmountable challenge.

But although this virus presumably originated in another mammal species (it is assumed to have once been a bat virus) it's not clear to me whether there's a real reservoir in other species today, the vast bulk of the world's infected seem to be humans.

In a virus that lacks a viable animal reservoir you can achieve eradication by "just" eliminating the virus in humans in each place and ensuring infected humans don't spread it into places where it was eliminated, a strategy that costs money but is final. That's where the previous SARS virus went - we eliminated it and it didn't come back, and of course it's why Smallpox is gone.

And eliminating SARS-CoV-2 is possible, because New Zealand did it. They had outbreaks in elderly care a year ago, and they locked down, tracked down every case, isolated every infected person, and eliminated the virus. All subsequent outbreaks have been connected to their border, if everybody had done likewise the virus would be gone. Of course that wasn't entirely realistic (other large islands like Great Britain could definitely have at least attempted this but they did not, but it's difficult to imagine North America or Russia achieving elimination without a vaccine) but with better tools now I think it could be attempted if the political existed, which I argue it does not.

The trickiest part about this virus for elimination from 2022 onward is maybe it's viable as a virus that doesn't cause much disease, especially in a vaccinated population. If it's infecting otherwise healthy adults and just causing sniffles for a week, once the pandemic headlines stop nobody will isolate and prevent onward spread. In much of the world (including the US) they'll even keep going to work and give it to colleagues as well as those they live with. Lots of coronaviruses thrive this way in humans.

> much in the way we come up with a new flu shot every year

I'm hoping that since it is a coronavirus, and not influenza, it won't mutate anywhere near fast enough to evade vaccines on a yearly basis. Right now SARS-CoV-2 is getting a best case environment for mutation. When a substantial portion of the world has been vaccinated, the mutation rate is going to drop significantly, and hopefully with perhaps one more iteration of the vaccine (given to the whole world, granted) we can dispense with this virus altogether.

Mutation rate for SARS-COV2 is about half of mutation rate of influenza viruses, so it still mutates pretty fast compared to DNA viruses or bacteria.

I can find only one source claiming it is half that of influenza. The consensus seems to be more like one quarter. And there is some nuance, because the way that influenza mutates is different, and gives it a bigger advantage in evading antibodies. The structure of the coronavirus does not share that property, which is why we haven't yet seen a mutation that can evade vaccination.

One quarter per base pair, one half per whole genome.

The same proofreading machinery which lowers its mutation rate, though, allows recombination when multiple infection happens. I would argue that gives this coronavirus a mutational advantage over influenza making up some of the difference in base pair mutation rate:


The reason why we haven't seen a true escape mutation is more to do with the fact that you need mutations at up to 20 epitopes on the spike protein to collectively arise, and one mutation alone won't do it, which is likely to eventually be costly to the virus and it would prefer to maintain the same fitness levels and spread in the totally naive population (at the same time though the mutations in spike which come at a fitness advantage that have been seen are worrisome because it means the virus still has room to move on the spike protein without negatively impacting fitness). It won't encounter enough selection pressure to achieve escape mutations until you start to see >70% of the population vaxxed or recovered. Influenza itself can takes several years to mutate and come back which you can see by the waxing and waning of 2009 H1N1, which has not been epidemic every year, so we wouldn't have expected an escape mutation by now even on paper.

Thanks for the detailed explanation, this is why I love HN.

Doesn't the virus mutate especially in people with asymtomatic cases and vaccinated indivuduals? There was this Gates Foundation virologist, Geert Vanden Bossche, who wrote an open letter to the WHO claiming that he was concerned that vaccination during s pandemic would cause super strains. Of course, there's no scientific consensuns on this, it's just one guy making controversial claims.

Anyway. We got vaccinated a week ago with AZ, blood clots or not, super strains be damned.

> But since eradication seems highly unlikely, I'm hoping that we'll find the basic vaccines we've come up with so far can be modified to target new variants

My understanding is that one of the major benefits of mRNA vaccines is how easy they are to both design and produce (although storage and transportation is a challenge). It seems likely we might need yearly boosters, and I think the mRNA vaccines will be up to the task.

An important, as of yet unresolved question, is whether those changed vaccines will lead to the generation of new antibodies vs. a boost of the existing ones, a phenomenon called original antigenic sin. Fingers crossed...

For those curious about Original Antigenic Sin [1].

It's basically the immune system keeping and using an old weapon that is no longer effective just because the intruder has the same haircut as his great great grandfather.

[1] https://en.wikipedia.org/wiki/Original_antigenic_sin

This is my biggest worry. I can't help but wonder (with a very uneducated and uninformed opinion here) if we are stoking or entering the next stage of an arms race.

I agree.

There is a natural balance, between host and virus and population, that keeps the mutability and lethality in check.

Basically a natural kind of population control. Vaccines and technology in general do in a sense change this dynamic.

It's possible that the immune system becomes decoupled and evolutionarily atrophied when an artificial immune system becomes the primary defense.

That was definitely a thought that passed through my head at some point, but the problem is, I question the premise. Where is the proof that it's a natural kind of population control -- what if it's potentially a driving factor of genetic fitness and evolution itself? Not to get too anthropocentric, but what if, grotesquely, there is a form of sentience to which we are merely the raw calories and nutrients for it to metabolize into something else?

I don't have a good enough bio background to give a great answer here. But I can reference a paper that has provoked all manners of thoughts on my end [1].

So if you take a read through that paper, perhaps you can begin to wonder what I am so nervous about. If vaccines previously mediated human evolution to some degree, what's going to happen when humans begin to seize control of that mediator? What's the runaway feedback loop look like?

[1] "Role of viruses in human evolution" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159740/

Seems unlikely when most minor illnesses dont have vaccines, and vaccines work by pretending to be the virus. If the immune system stopped working against normal viruses it would probably stop working against vaccines too.

Just to be clear (to address the downvotes) I am _NOT_ anti-vaccine. Just contemplating the affect vaccines have in immune system evolution (in the distant future).

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