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Good News on T-Cell Response

There are several recent preprints and publications that bear on the T-cell immunity story for the coronavirus pandemic, and I wanted to highlight these, since it’s been a big part of the story that’s needed more information for a long time now.

Here, for one, is a multi-institute study from the UK. The authors are looking at 100 COVID-19 patients over a six-month period and correlating the antibody and T-cell responses. What they see is what you’d want to see: the T-cell responses appear to be durable over that time. They do seem to be correlated with the severity of the infection – responses were definitely higher in the people who had experienced symptoms, as opposed to asymptomatic cases. The T-cell response against the coronavirus nucleoproteins seemed to correlate with the degree of later decline of the antibody response to those proteins, but this did not hold true for the response to the Spike protein (the two were uncorrelated – antibody responses to the Spike protein could go down, while T-cell responses remained). 80% of the patients who had mild-to-moderate infection, however, did have Spike-specific cellular responses at the six month time point. For T-cell aficionados, the response was mostly (about 2:1) CD4+ cells with IL-2 cytokine expression, as opposed to CD8+ cells. Both types showed both Spike-directed and non-Spike-protein-directed responses, but the CD8+ were more biased towards the various non-Spike proteins.

Overall, this work suggests that people who have experienced at least some degree of symptomatic infection should have reasonably long-lasting T-cell responses. There does seem to be a “set point” for these, correlating with that severity. What will tie this to the vaccine efforts will be the data on the T-cell responses induced by the vaccines themselves (which as of now are completely directed towards a Spike protein response), as compared to the wild-type viral infection. And I presume that we’ll be getting those numbers from the ongoing trials.

Now here’s another new preprint from a different multicenter UK team that has some really interesting correlations. It’s a prospective study looking at 2,826 front-line workers there – they’ve been measuring their T-cell levels (using a new assay from Oxford Immunotec) and their antibody profiles since June and seeing who comes down with coronavirus infection over time. All the workers who were seropositive at the start (displaying antibodies against coronavirus proteins) also had robust T-cell response levels. In the seronegative group, there were some with robust T-cell numbers and some without. Split up another way, of the people in the study with strong T-cell responses to the coronavirus proteins, only about 55% of them had detectable antibodies to those proteins. Over time, 20 of the overall weak-T-cell group were infected with the virus, while zero of the strong T cell response group were (p = 0.006).

That suggests that there may indeed be some protective T-cell immunity out there that is being missed by a focus on antibody levels (as has been suspected), but it also says that you can’t just extrapolate this to the whole population by any means: we don’t all have T-cells ready to go. But if you do, you may have a substantial amount of protection, and this might be detectable by a relatively simple assay.

That last point has been the holdup in this area: the story has been all about antibodies because the assays for those are far, far easier to set up. T cell assays are very labor intensive indeed, and the sample sizes in the papers on them tend to be in the dozens. But as you can see, the Oxford Immunotec people are trying to improve that, and so is a company called Adapative Biotechnologies here in the US (and there are others). They have a big write-up in the New York Times this week, and it’s a good article. A quote from an immunologist in it sums things up well: “There has. . .never been great demand for wading into the intricacies of T cell tests.” Adaptive’s recent work on a population in Italy suggests that its test is definitely better at determining whether a person has had a previous coronavirus infection (as opposed to antibody measurements), and if we put that together with the other papers mentioned, it could be that this extends to saying how much protection these people retain.

So the story is coming together. And just as vaccine work is never going to be the same after the huge amounts of work during this pandemic, it looks like T-cell research is never going to be the same, either. They’re both going to be better, faster, and more detailed, and that’s good. Because we’re going to need all this again some day.

23 comments on “Good News on T-Cell Response”

  1. Steve Scott says:

    That’s encouraging news for the under-65 group. The first study referenced above, says.. “Among the 100 donors, … a median age of 41.5 years (22–65 years).”
    I don’t know if there are any clues yet on how effective the long term T-cell response will be for the vulnerable elderly population, among the various vaccine candidates. As has been pointed out, hopefully we’ll find out more from the Phase III trial results.

  2. Hopeful Layman says:

    My memory tells me that early reports from Oxford/AZ indicated that their vaccine stimulated very robust T-Cell development. Unless I’m mistaken, Novavax reported something similar early on. Have those predictions been borne out, or do we know either way (i.e., with the emphasis on antibody levels, have T-Cells been relegated to the category of “hopefully beneficial side effects” in the vaccines currently being tested?

  3. Joe says:

    Link to second study publication?

    1. Marko says:

      SARS-CoV-2 responsive T cell numbers are associated with protection from COVID-19: A prospective cohort study in keyworkers

      https://www.medrxiv.org/content/10.1101/2020.11.02.20222778v1

      I tracked it down through the Oxford Immunotec “News”section.

  4. cynical1 says:

    Yes, with regard to the second study publication you said that “In the seronegative group, there were some with robust T-cell numbers and some without”. What percentage of the seronegative group had robust T-cell numbers? (I could also figure it out from the percentage who were seropositive by antibody initially.)

    1. Chris Phillips says:

      Thanks to Marko for the link.

      So “the 2,672 unselected participants were divided into those with higher [T-cell] responses (n=669, 25.4%; median 30 spots (IQR 18,54)) and those with low responses (n=2016, 76.7%, median 3 (IQR 1,6)) … Of the participants with higher T cell responses, 367 (53%) had detectable antibodies against the N or S proteins.”

      So I wonder what that means. Given the reported rates at which antibodies fade, it’s not really clear from these results whether significant numbers of people who have never been exposed to the virus will have this high T-cell response.

      Of course it’s excellent news that 25% of this sample in the UK have a protective high T-cell response. But given that the sample will be biased towards exposure to the virus, I think it’s believable that 25% could be the number who have been infected, and that the strong T-cell response won’t been seen in the absence of infection.

      1. cynical1 says:

        Thanks Chris. I think what that means is that 13% of the entire sample already have high T-cell responses because they were already infected (and showed positive antibody response) and 12% of the entire population is immune from previous infection with another coronavirus similar enough to SARS-CoV-2 that T-cells provide cross over immunity. Since the authors speculated that it was likely one of the coronaviruses that cause the common cold, they may want to look for antibodies to that virus in that population. Then we could also look at the people who have had COVID-19 and if none of them have antibodies to the common cold coronavirus, we’d have a pretty strong case that the cold one provides immunity to COVID-19. Then we could just infect the entire planet with that coronavirus, everyone gets a cold, and we are done. Sounds simpler then it is but it also sounds like it might work. I also wouldn’t mind knowing if I had antibodies to the other coronavirus.

        1. Marko says:

          “….Since the authors speculated that it was likely one of the coronaviruses that cause the common cold, they may want to look for antibodies to that virus in that population. ”

          The authors missed the boat , IMO , by not doing a comprehensive antibody screen with titers for the seasonal coronaviruses. That could have really tied the picture together nicely if it turned out that the high T-cell responders who were not previously infected with COV2 had a high titer to one of the other hCOVs. As it stands , it’s still possible that those high responders had an asymptomatic COV2 encounter for which they didn’t seroconvert , but which was still sufficient to prime the T-cell response.

          1. Mark Coley says:

            The ideal experiment for me would be to make comparisons of antibody titres for 229E and NL63 (the two common alphacoronaviruses), OC43 and HKU1 (the two common betacoronaviruses) along with SARS-CoV-2, together with T cell responses to unique peptides that are found on each of these viruses, along with a clinical history of a covid-19-like illness this year, possibly with a positive PCR swab. I wonder if there are many people around who have robust T cell responses to the commonly circulating ones (eg OC43 and 229E), and who have been exposed to SARS-CoV-2 repeatedly in recent months, yet have no specific T cell response to this virus nor any specific antibodies to it. Such people (if they exist) may never have been swabbed if symptoms never warranted it but they may have had protection from serious illness. And if infected mildly they may have been able to pass it on.

  5. ScientistSailor says:

    Does this imply that children, who mostly have none to moderate infections are not developing lasting immunity?

    1. Hopeful Layman says:

      I’m a little confused about children, too. Weren’t we hearing for a while that they actually carry heavier viral loads than adults, and so are at higher risk for spreading when they come in contact with older people? If that’s the case, I’d guess that their post-infection antibody level would also be pretty high. But I’m not sure whether this theory is still widely accepted.

  6. Incajb says:

    I wonder if we are shooting ourselves in the foot by using dexamethasone in COVID-19 patients. Could we be blunting CD4+ response decreasing prolonged immunity?

    Generally, the data for people with HIV indicates that if their CD4+ count is higher (but still lower then HIV negative individuals), then they fair as well as the general population. It is also known that steroids do not alter CD4+ cell recovery in this population in the first months of antiretroviral therapy.

    1. John Wayne says:

      Fascinating question. Don’t give the virus any ideas.

  7. TPO says:

    There is nothing whatsoever new about the Oxford Immunotec T cell assay. It’s a renamed cytokine ELISpot assay, which has been around for nearly 25 years.

  8. JensML says:

    Off topic: Scientific paper on danish mink from Statens Serum Institut can be found at: https://files.ssi.dk/Mink-cluster-5-short-report_AFO2

    1. Crni says:

      Migth actually be on topic. No T-cell response checked, only antibody response decreased. Looks like the cull has been halted and rightly so.

      1. Some idiot says:

        A very good and open question… However it is worthwhile pointing out that that SSI’s _major_ concern was not this particular strain (the so-called “cluster 5”), but more generally the facts that (a) mink are unusually susceptible to COVID-19, and (b) the virus hops extremely easily between mink and humans (the leader of the centre, in an interview a few days ago, was at pains to point out that amongst the animals investigated, mink was essentially unique in this respect). Therefore, their main concern was that with such a huge, closely-connected reservoir of infection, with a very significant evolutionary pressure to create infective strains that would evade antibodies, it was considered highly likely that it would lead to further mutations that could cause problems to humans, regardless of whether or not they had been vaccinated (or had previously had disease). So, in a way, the “cluster 5” was more or less “just” a proof of principle.

        But your question is a good one, as regards T-cells. I would guess that they would be considering this as well, but probably don’t have results yet.

        On a more personal not, it saddened me significantly to see (essentially) a whole industry wiped out. I have no great love of the fur industry, but that is irrelevant in this situation. My ancestors came from farming, and I know parts of that (not fur, but…) industry pretty well. Things that have been in families for generations; farmers trying to keep their breeding stock during the really bad times, nurturing them, creating through breeding the best stock for the purpose… All gone due to circumstances out of their control. Heartbreaking. My heart goes out to them. I had considered other alternatives, for example if it were possible to keep breeding stock in an area with good ventilation, and at least 2 m distance to each other. I have no idea whether or not this has been considered. But I hope someone is thinking about it…

        1. Crni says:

          Yeah I am in a way not a big fan of the fur industry, but the animals are there and people depend on them for their livelihood. So I do not see why the animals would be culled so drastically without any other attempts to solve the situation, especially since effect on the T-cell response does not seem to be known.

          17 million mink in Denmark being 40% of the worldwide industry gives ~43 million mink worldwide against currently already confirmed 52million human COVID cases. The human number will likely double within the next year at least. So the mink industry is not an order of magnitude higher mutation incubator, but might contribute, sure.

  9. Great article, thank you.

  10. steve says:

    The Oxford Immunotec assay is not a new one, it’s also an Elispot. The problem is that T cell responses are highly individual being dependent on MHC haplotype and the peptides presented. You therefore need a functional test, which means incubation of T cells with antigen, which means you can’t develop a CLIA-waved rapid test like you can with antibodies. If the T cell response is important then Pfizer wins over Moderna as the former induces a CD8 response whereas the latter doesn’t (be careful about reports only citing CD4, these may just be helper cells for antibody and do not represent the virucidal component of T cell immunity, which is CD8). Immunology is not for the faint-hearted.

  11. Lane Simonian says:

    A seeming conundrum is how you can have too little immune response early on and too much immune response later on. Part of the answer may lie in T cell dysfunction due to nitration, especially in those with pre-existing conditions (such as in neurodegenerative diseases, cancer, and in diabetes).

    https://pubmed.ncbi.nlm.nih.gov/10092790/

    The flip side to this conudrum is how can certain plant compounds (in panax ginseng, for example) both “boost” your immune system (by partially reversing T cell dysfunction) and protect against cytokine storms (by inhibiting oxidation). Identifying the most effective of these compounds could potentially lead to a treatment for both the early and late stages of a coronavirus infection.

    1. theasdgamer says:

      If a person’s immune system is incompetent, perhaps due to zinc or vitamin D deficiency, then it will be more likely to overreact late in the game. However, it seems that most covid deaths are due to organ failure due to hypoxemia due to microemboli in capillaries.

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