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Summary
SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. We here systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits robust, broad and highly functional memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.
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More Good News on T-Cells
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Last: 5 yr ago by buffalo chip
That appears to be great news. I have thought this is one possibility why the herd numbers can be low.
This really is great news!
Now that is unequivocally good news. Something that is quite rare in most Covid studies and analysis.
Unfortunately from a public heath perspective, T cell response is a lot harder to check than circulating antibodies.
Unfortunately from a public heath perspective, T cell response is a lot harder to check than circulating antibodies.
Ok, if this is true, immunity to this disease is very likely far greater than our current estimates.
Antibodies go away about two weeks after the disease.
What this report is suggesting is that everyone that is exposed to the disease develops T-cell immunity whether they developed symptoms or not.
Since we are only testing for antibodies, there is likely a great number of people with immunity, who's T-cells fought off the disease after exposure without getting sick, who we are not picking up in any of our tests.
This explains the behavior of the virus much better than current models. The 20% or so infected that it seems to take to get to herd immunity seems way too low. But if we are only catching one 1 out of 3 or 1 out of 4 people that actually have developed immunity through exposure that didn't lead to a broad infection, then that 20% of infected people looks really high.
Antibodies go away about two weeks after the disease.
What this report is suggesting is that everyone that is exposed to the disease develops T-cell immunity whether they developed symptoms or not.
Since we are only testing for antibodies, there is likely a great number of people with immunity, who's T-cells fought off the disease after exposure without getting sick, who we are not picking up in any of our tests.
This explains the behavior of the virus much better than current models. The 20% or so infected that it seems to take to get to herd immunity seems way too low. But if we are only catching one 1 out of 3 or 1 out of 4 people that actually have developed immunity through exposure that didn't lead to a broad infection, then that 20% of infected people looks really high.
It takes a special kind of brainwashed useful idiot to politically defend government fraud, waste, and abuse.
But where there is a will (and $$$ to be made) there is a way. Could be even more important than an untested vaccine. I would certainly rather know if I had T-cell immunity instead of being int he initial groups getting any vaccine.amercer said:
Unfortunately from a public heath perspective, T cell response is a lot harder to check than circulating antibodies.
This part is interesting:
We detected potentially cross-reactive T cell responses directed against either the spike or membrane proteins in a total of 28% of the healthy individuals who donated blood before the pandemic, consistent with previous reports (Grifoni et al., 2020; Le Bert et al., 2020), but nucleocapsid reactivity was notably absent in this cohort (Figure 3A and Figure S4A, B).
The highest response frequencies against any of the three proteins were observed in convalescent individuals who experienced severe COVID-19 (100%). Progressively lower response frequencies were observed in convalescent individuals with a history of mild COVID-19 (87%), exposed family members (67%), and healthy individuals who donated blood during the pandemic (46%) (Figure 3A).
BD is blood donor
Exp is exposed
MC is mild Covid
SC is severe Covid
We detected potentially cross-reactive T cell responses directed against either the spike or membrane proteins in a total of 28% of the healthy individuals who donated blood before the pandemic, consistent with previous reports (Grifoni et al., 2020; Le Bert et al., 2020), but nucleocapsid reactivity was notably absent in this cohort (Figure 3A and Figure S4A, B).
The highest response frequencies against any of the three proteins were observed in convalescent individuals who experienced severe COVID-19 (100%). Progressively lower response frequencies were observed in convalescent individuals with a history of mild COVID-19 (87%), exposed family members (67%), and healthy individuals who donated blood during the pandemic (46%) (Figure 3A).
BD is blood donor
Exp is exposed
MC is mild Covid
SC is severe Covid
exposure in NYC might be much much higher than ~25%
Solid news. Looking forward to reading the report.
Unless I'm mistaken the vaccines in production don't elicit T-cell response(?)
Unless I'm mistaken the vaccines in production don't elicit T-cell response(?)
I think it's an open question on the vaccine T cell response, but I would be surprised if the winners didn't
Could be wrong, but I thought I remember seeing that the Moderna vaccine elicited a strong Antibody and T-Cell response
Actually it looks like Pfizer ...
https://www.fiercebiotech.com/biotech/pfizer-reports-strong-t-cell-response-to-covid-19-vaccine
https://www.fiercebiotech.com/biotech/pfizer-reports-strong-t-cell-response-to-covid-19-vaccine
Thanks. There are several in the hunt. I'm not up to speed on their differences.
I will say one drawback of this paper is the inability to really distinguish between a T cell response specific to Covid-19 and one that is cross reactivate from exposure to other coronaviruses.
A big percentage of the T cell response found in the exposed family member cohort could be cross reactive and not COVID-19 specific. It is still an open question how protective those are.
It is reassuring that mild cases give a robust response. I got no doubt that immune response is Covid-19 specific and will protect against reinfection.
A big percentage of the T cell response found in the exposed family member cohort could be cross reactive and not COVID-19 specific. It is still an open question how protective those are.
It is reassuring that mild cases give a robust response. I got no doubt that immune response is Covid-19 specific and will protect against reinfection.
I don't think we have ruled out the possibility the difference between a mild and severe case is some kind of immuno-pathology. In other words, severe disease is caused by an immunological mistake. Perhaps overreaction or a failure to regulate and ramp down an otherwise appropriate immune response causing a cascade of failures. This has all kinds of ramifications for vaccines and treatments. Worse would be discovering that a quirk of the virus causes the pathology, but only in some.
If the T cell study and this type of quantitative analysis holds, it is over (as a pandemic, etc.). Levett may prove to be correct.
We do not need no stinking Princeton PHD to tweet about this good news!BusterAg said:
Ok, if this is true, immunity to this disease is very likely far greater than our current estimates.
Antibodies go away about two weeks after the disease.
What this report is suggesting is that everyone that is exposed to the disease develops T-cell immunity whether they developed symptoms or not.
Since we are only testing for antibodies, there is likely a great number of people with immunity, who's T-cells fought off the disease after exposure without getting sick, who we are not picking up in any of our tests.
This explains the behavior of the virus much better than current models. The 20% or so infected that it seems to take to get to herd immunity seems way too low. But if we are only catching one 1 out of 3 or 1 out of 4 people that actually have developed immunity through exposure that didn't lead to a broad infection, then that 20% of infected people looks really high.
Explains the rapid fall of cases in about 12 weeks after major infections kick in.
Without lockdowns this would be over already. Just like in Sweden.
By over I mean very low new infection rates.
Without lockdowns this would be over already. Just like in Sweden.
By over I mean very low new infection rates.
Glad the focus is shifting to the T-cell response and away from antibodies which is all anyone would focus on in May-June-July and was misguided.
But, I'd caution on trying to interpret what this means for infection rates and potential herd immunity. The outlook from this study and what the data says speaks more to possibilities of reinfection. It looks like this coronavirus will have the same fate as other coronaviruses of our past -- strong, severe outbreak with disease severity decreasing over time to the point that it is still circulating, but becomes background like other coronaviruses that give the common cold.
Most vaccine candidates have shown a strong T-cell response, but there is one in particular that is lacking that people continue to ignore.
But, I'd caution on trying to interpret what this means for infection rates and potential herd immunity. The outlook from this study and what the data says speaks more to possibilities of reinfection. It looks like this coronavirus will have the same fate as other coronaviruses of our past -- strong, severe outbreak with disease severity decreasing over time to the point that it is still circulating, but becomes background like other coronaviruses that give the common cold.
Most vaccine candidates have shown a strong T-cell response, but there is one in particular that is lacking that people continue to ignore.
The total fatality rate of this disease compared to immunity to this disease is going to have to be measured in basis points by the time we are done.
It takes a special kind of brainwashed useful idiot to politically defend government fraud, waste, and abuse.
I agree we shouldn't be over interpreting this.
It's really good news that mild and asymptomatic cases are probably protected from reinfection. I don't think you can necessarily extrapolate the findings in this study to national infection rates.
It's really good news that mild and asymptomatic cases are probably protected from reinfection. I don't think you can necessarily extrapolate the findings in this study to national infection rates.
I haven't spent much time on following the vaccine race. Which vaccine are you suggesting has not shown a good t-cell response?
We won't need a vaccine in a few months. But if it makes people feel more safe that's great.
Moderna, Pfizer, and AstraZeneca(Oxford) all have demonstrated t-cell response.Fitch said:
Thanks. There are several in the hunt. I'm not up to speed on their differences.
https://www.evaluate.com/vantage/articles/news/trial-results/covid-19-vaccine-contest-turns-t-cell-responses
I suspect it is fairly common for vaccines to elicit a T cell response in addition to antibodies, just no one has really looked before. The technology to do a T cell analysis at scale is relatively new,
Why do you think cross reactive matters? T cell receptor binds SARS-COV2 sufficiently to trigger an immune response or it doesn't. Doesn't matter if it does the same for SARS or others.amercer said:
I will say one drawback of this paper is the inability to really distinguish between a T cell response specific to Covid-19 and one that is cross reactivate from exposure to other coronaviruses.
A big percentage of the T cell response found in the exposed family member cohort could be cross reactive and not COVID-19 specific. It is still an open question how protective those are.
It is reassuring that mild cases give a robust response. I got no doubt that immune response is Covid-19 specific and will protect against reinfection.
It isn't like the immune system is running some competition assay and only triggers on the virus it binds most tightly to.
Thanks BiochemAg... I have been waiting for some of the anointed Ags (a good thing) to comment on this thread. The potential beneficial impact of the Sweden study's findings is extremely high. I appreciate your professional perspective being added to this thread.
It matters because it would be nice to know if mild/asymptomatic cases actually do result in a robust protective immune response. I'm not sure the in vitro T cell activation assay with spike peptides is necessarily predictive of protective immune response. It's VERY suggestive, and if you've had a confirmed infection with the virus in question I would believe it to be predictive.
We don't know how protective cross reactive T cells from other coronaviruses infections are. They seem to be common, (which again might be good, but we don't know) and since they are common it confounds the analysis here some. The authors can't show if the exposed family members actually got Covid and were asymptomatic, if the were resistant to catching it at all because of cross reactive T cell, or if they weren't actually exposed to an infectious dose of virus.
I'm happy to see that even mild infections probably protect from reinfection, but I think there are some epidemiological questions that this study can't answer. It's still a great study though.
We don't know how protective cross reactive T cells from other coronaviruses infections are. They seem to be common, (which again might be good, but we don't know) and since they are common it confounds the analysis here some. The authors can't show if the exposed family members actually got Covid and were asymptomatic, if the were resistant to catching it at all because of cross reactive T cell, or if they weren't actually exposed to an infectious dose of virus.
I'm happy to see that even mild infections probably protect from reinfection, but I think there are some epidemiological questions that this study can't answer. It's still a great study though.
I think you are confusing two things. If there is a lot of cross reactivity to "other coronaviruses" it could mean you already had them before COVID, meaning a Positive test would not indicate you previously had COVID 19. Same with the antibodies if there is cross reactivity there.amercer said:
It matters because it would be nice to know if mild/asymptomatic cases actually do result in a robust protective immune response. I'm not sure the in vitro T cell activation assay with spike peptides is necessarily predictive of protective immune response. It's VERY suggestive, and if you've had a confirmed infection with the virus in question I would believe it to be predictive.
We don't know how protective cross reactive T cells from other coronaviruses infections are. They seem to be common, (which again might be good, but we don't know) and since they are common it confounds the analysis here some. The authors can't show if the exposed family members actually got Covid and were asymptomatic, if the were resistant to catching it at all because of cross reactive T cell, or if they weren't actually exposed to an infectious dose of virus.
I'm happy to see that even mild infections probably protect from reinfection, but I think there are some epidemiological questions that this study can't answer. It's still a great study though.
That is not the same as affinity. Yes, could be weakly binding and wouldn't help much. Haven't looked at the study in depth, but hopefully they controlled for low affinity reactions somehow. But the important question for immunity is do they bind well enough to trigger a strong immune response.
As an example, we have known for months that antibodies to SARS-CoV cross reaction with SARS-CoV2. This isn't at all surprising given the proteins of the two viruses are ~95% identical. So someone with SARS antibodies would test positive for COVID19 antibodies but may have never had COVID19.
Ultimately, I don't think these (t cell activation and antibody) test are necessarily good at telling if you had the virus, but if you activate the T cells with SARS-CoV2, you get an immune response. And that would indicate immunity to the virus, regardless if that came from exposure or before.
I'm making two separate points. The first is agreeing with your last point above. A T cell response doesn't prove you were infected with Covid19.
The second point though is that we still don't know if the T cell responses we see from unexposed individuals are protective. It's not unreasonable to think they might be, but there seems to be a huge variability in the course of disease, and we know that an overactive immune response is a hallmark of serious cases.
The second point though is that we still don't know if the T cell responses we see from unexposed individuals are protective. It's not unreasonable to think they might be, but there seems to be a huge variability in the course of disease, and we know that an overactive immune response is a hallmark of serious cases.
There are definitely some causation vs correlation questions related to interpreting these results. For instance, in the plots included up thread, is the lower "levels" of CD8 (row D above or figure 4D in the paper) in the severe over the moderate disease cases a cause, a result, suggestive of a poor immunological response that contributes to severe cases, or something else?
https://www.nature.com/articles/s41586-020-2550-zamercer said:
I'm making two separate points. The first is agreeing with your last point above. A T cell response doesn't prove you were infected with Covid19.
The second point though is that we still don't know if the T cell responses we see from unexposed individuals are protective. It's not unreasonable to think they might be, but there seems to be a huge variability in the course of disease, and we know that an overactive immune response is a hallmark of serious cases.
On the second point, this paper demonstrated immune activation in response to NSP7 and NSP13 by quantifying IFN gammas and TFN levels post exposure. Note NSP7 and NSP13 are well conserved across coronavirus, which isn't all that surprising given they are a significant player in viral replication. I think that reasonably demonstrates the T cells interact strongly enough with those peptides to get an immune response. Since those are viral surface proteins, it might be reasonable to wonder if those proteins would be presented to T cells by an infected cell. Given there is an entire mechanism for presenting fragments of the proteins being made in the cell and people have t-cells specific to these NSP7 and 13 peptides, it seems clear that they do get presented by the MHC complex to the t-cells.
Interestingly, the paper notes that NSP7 and 13 are produced very early by the cell when infected (they are needed to make all the other things) and that N and S are produced much later when assembling the virus. The authors hypothesize that if the T cells catch the infected cell early with NSP7 and NSP13 and kill it, the virus never really gets a chance to reproduce. Having a strong response to these early proteins could very well kill off the initially infected cells and prevent viral reproduce, thus never really getting to the point of having symptoms. Might very well explain asymptomatic cases, whereas those who get sick might not have a strong cross reactive response.
There is another study going on that is looking at the DNA of t cells and B cells to see if they can identify markers indicative of the severity of the disease. In theory, if T cells to NSP7/NSP13 did stop the infection before it could take hold, the sequences for those receptors should be markers of asymptomatic cases and lack of those might indicate the potential for a severe response. I am really curious to see how that study turns out.
That's very interesting.
I guess the bad news is that those non structural proteins aren't going to be part of the vaccine. Hopefully a response against the spike is as effective.
I guess the bad news is that those non structural proteins aren't going to be part of the vaccine. Hopefully a response against the spike is as effective.
The authors also noted that for those recovered from COVID/SARS had a dominant N protein response whereas those unexposed and asymptomatic cases were dominated by the non surface proteins, surface reactive immune response may be able to intercept the viruses before they infect cells whereas the non structural proteins would target recently infected cells.amercer said:
That's very interesting.
I guess the bad news is that those non structural proteins aren't going to be part of the vaccine. Hopefully a response against the spike is as effective.
It does create an interesting new avenue for vaccines. Imagine If you could get a flu vaccine that triggered a strong T cell response to non-structural protein that is highly conserved across influenza A. Maybe you could skip the "guess which flu strains will be hot next year" game and just get one shot for several years.
That would be a truly wonderful benefit of experiencing this whole ordeal! The billions and billions of dollars going into research with regard to COVID 19 could have some unexpected upside.BiochemAg97 said:Imagine If you could get a flu vaccine that triggered a strong T cell response to non-structural protein that is highly conserved across influenza A. Maybe you could skip the "guess which flu strains will be hot next year" game and just get one shot for several years.amercer said:
That's very interesting.
I guess the bad news is that those non structural proteins aren't going to be part of the vaccine. Hopefully a response against the spike is as effective.