SARS-CoV-2 T-cell epitopes define heterologous and COVID-19-induced T-cell recognition

The SARS-CoV-2 pandemic calls for the rapid development of diagnostic, preventive, and therapeutic approaches. CD4+ and CD8+ T cell-mediated immunity is central for control of and protection from viral infections[1-3]. A prerequisite to characterize T-cell immunity, but also for the development of vaccines and immunotherapies, is the identification of the exact viral T-cell epitopes presented on human leukocyte antigens (HLA)[2-8]. This is the first work identifying and characterizing SARS-CoV-2-specific and cross-reactive HLA class I and HLA-DR T-cell epitopes in SARS-CoV-2 convalescents (n = 180) as well as unexposed individuals (n = 185) and confirming their relevance for immunity and COVID-19 disease course. SARS-CoV-2-specific T-cell epitopes enabled detection of post-infectious T-cell immunity, even in seronegative convalescents. Cross-reactive SARS-CoV-2 T-cell epitopes revealed preexisting T-cell responses in 81% of unexposed individuals, and validation of similarity to common cold human coronaviruses provided a functional basis for postulated heterologous immunity[9] in SARS-CoV-2 infection[10,11]. Intensity of T-cell responses and recognition rate of T-cell epitopes was significantly higher in the convalescent donors compared to unexposed individuals, suggesting that not only expansion, but also diversity spread of SARS-CoV-2 T-cell responses occur upon active infection. Whereas anti-SARS-CoV-2 antibody levels were associated with severity of symptoms in our SARS-CoV-2 donors, intensity of T-cell responses did not negatively affect COVID-19 severity. Rather, diversity of SARS-CoV-2 T-cell responses was increased in case of mild symptoms of COVID-19, providing evidence that development of immunity requires recognition of multiple SARS-CoV-2 epitopes. Together, the specific and cross-reactive SARS-CoV-2 T-cell epitopes identified in this work enable the identification of heterologous and post-infectious T-cell immunity and facilitate the development of diagnostic, preventive, and therapeutic measures for COVID-19.

Here is the full piece, by Annika Nelde,, via Jackson Stone.  Or from the paper, here is a simpler bit:

At present, determination of immunity to SARS-CoV-2 relies on the detection of SARS-CoV-2 antibody responses. However, despite the high sensitivity reported for several assays there  is still a substantial percentage of patients with negative or borderline antibody responses and thus unclear immunity status after SARS-CoV-2 infection34. Our SARS-CoV-2-specific T- cell epitopes, which are not recognized by T cells of unexposed donors, allowed for detection of specific T-cell responses even in donors without antibody responses, thereby providing evidence for T-cell immunity upon infection.

Big (and good news) if true.


What on earth do these words mean?

Economists play scientists.

the part of an antigen molecule to which an antibody attaches itself.
I had to look it up. It was not covered in Immunology for Dummies.

They are claiming to have found the protein sequence which will grab that covid shell and chomp a couple of the supporting pillars, and the whole covid shell collapses. They further imply it might lead to a vaccine, but mostly imply they have an antibody formula. Is it monocolonal which means the anti-body will sit in a culture and simply replicate itself to make a nice noise spray. I dunno, haven't read it.

Step one, but a nice step one. Tyler got a good pick.

Be honest Tyler, you're as confused by this as the rest of us.

It essentially means that probably a lot of people already have resistance to COVID-19 due to previous infections with other members of the coronavirus family. It also means that the seroprevalence studies conducted to date are not sufficient to establish where herd immunity stands- the antibody tests are underestimating immunity to some degree, and a lot of the stories about those confirmed infected, but lacking measurable antibody levels probably do have immunity of another kind that is more robust than that conferred by experience with the other coronviridae members.

At least, that is how I read the abstract.

Thanks for that clear explanation. Good news indeed if true.

Good news, and that confirms what was clear from epidemiological observation, that we have attained almost herd immunity in many places (NY area, Paris area, Northern Italy, etc.)

Before believing we have attained almost herd immunity in many places (NY area, Paris area, Northern Italy, etc.) One can certainly hope so, but opinions matter nothing to a virus.

Not to mention the below, cut and paste from another one of my it realistic to assume 29%-80% of the population has been infected with C-19 virus, when the official stats say only 8% have been infected?

For "Herd Immunity" to happen you need to have a population infected comprising: 1-1/R0, where R0 =1.4 to 5.7 for the Covid-19 virus. R0 changes depending on social distancing. For R0=1.4, you need about 29% of the population infected. For R0=5.7 (no social distancing assumed), you need about 82% of the population infected. If the USA has indeed 25M Covid-19 infected people (either past or presently infected) then it is nowhere near to herd immunity, as presently a mere 25/330 = 8% of the population in the US has been infected with C-19 say the official stats.

There is a chicken and egg problem here. If we don't really know how many people have been infected then we don't really know what rho is.

Ro is estimated at the beginning of the epidemic ( with nobody immune) from the transmissibility characteristics. Most papers out of China placed it at 2.4 -2.6
The effective reproduction number Re depends on the number of susceptible, the length of time infectious, and conditions on the ground, for example social distancing, quarantining , wearing masks.
We know that just normal distancing measures ( not a lockdown) and wearing masks can reduce transmissibility by at least 30 %, so it's not a stretch that given social distance measures, Re would be at 1.5 or below.
In Germany during the lockdown it was estimated most of the time at below 1 , ~ 0.9

@Catinthehat - as you know, R0 1. The high range of R0 of 5.7 was from a paper, cite below, from a model based on Wuhan. Not sure what social distancing, if any, the Wuhan citizens practiced; I assume very little since this was an early paper and people did not understand C-19 much early on. There's a recent model, as you may know, where R0 < 1 if everybody in public (both infected and non-infected) wear good masks, but politically that's not going to happen in the USA. So a further lockdown is needed unless you wish to infect up to 82% of the country (or at least 29%)

Cite: COVID-19 Outbreak Associated with Air Conditioning in Restaurant, Guangzhou, China, 2020, by Steven Sanche1, Yen Ting Lin1, Chonggang Xu, Ethan Romero-Severson, Nick Hengartner, and Ruian Ke

WordPress doesn't like less than zero signs due to an obscure software taboo against such bug-inducing entries...what I say is "as you know, R0 is less than zero when a disease is dying out due to non-pharmacological interventions like quarantine" The rest of the post is reasonably clear.

The US is not homogeneous of course. The conditions in Wyoming are not the same as in NYC.
Herd immunity has been achieved in NYC already. With 20 to 25% infected as we have easily in the Bronx or Staten Island , it's enough.
Because there is a subset of people as hinted to by this paper and others who are effectively immune. They can mount a robust innate + T -cell mediated response and clear the virus quickly. They are the hardly susceptible/ hardly infectious,
Children are broadly in this category. In the updated Vo/Italy study they could not find an infected under 10 year old, (unlike the rate in the general population ) even though some of them lived in infected households. Similarly in the Iceland study.
There are many papers on the under representation of children in infection rates.
So tallying the infected and adding the effectively immune and keeping R at 1.5 and lower ( some social distancing + masks) is enough to slow down the virus dramatically ( see the plummeting daily new cases in NYC )

'Herd immunity has been achieved in NYC already.'

The virus has not even been around for a year. At a minimum, at least wait until winter is in full swing before making such a prediction.

Absolutely not .
There was already 21 % seropositve in late April in NYC

We have precisely no idea how long any immunity lasts after infection. Just as it appears that air conditioning is a major driver of summer infections causing a reverse seasonality as opposed to the anticipated slowdown in infections, maybe let us wait and see how long immunity/resistance lasts before making any statements concerning the second half of the first year of this pandemic.

There is no evidence whatsoever that influenza doesn't turn people into giraffes at midnight on Christmas day on years ending in "021". For this reason I urge that we take the precaution of increasing doorway height nationwide.

We know it last at least 3 months. We haven't seen any reinfections. With SARS-CoV, antibodies were persistent for two years then declining. This is likely the case with SARS-CoV-2
You seem to be of the mind, that we should wait years, gather all the data , and only then start making inferences from it.
It doesn't work that way.

That is not quite what the abstract says. The main conclusion from the paper is that patients who have a stronger immune response from a single epitope (the part of the virus where the antibody binds) tend to have a more severe case of COVID-19. Those with less sever COVID-19 cases had a greater diversity in their immune response. In other words, their immune system recognized multiple parts of the virus. This has implications for treatments and vaccines. A successful vaccine may need to induce an immune response against multiple parts of the virus.

As to the comment about existing immunity, the authors observe that patients never exposed to SARS-Cov-2 have some have antibodies that recognize part of the SARS-Cov-2 virus, likely from overlap from past coronavirus infections. That does not mean they have immune protection from the virus, but it does mean that antibody-based diagnostics will be more challenging to develop. A poorly designed test may be misled by that cross-reactive antibody response.

Regarding your second paragraph. I don’t think you meant to use the word “ antibodies”. Nobody has pre-existing antibodies to SARS-CoV-2 as far as we know.
Membrane bound antibodies are the antigen receptors of B lymphocytes.
They can recognize many types of chemical structures ( proteins , polysaccharides ,lipids, nucleic acids), T cells can only recognize peptides displayed by MHC molecules on antigen producing cells (APC).
The authors say: “Our SARS-CoV-2-specific T- cell epitopes, which are not recognized by T cells of unexposed donors, allowed for detection of specific T-cell responses even in donors without antibody responses, thereby providing evidence for T-cell immunity upon infection.”
Their T-cell epitope response tests can differentiate between epitopes linked to a previous HCoV exposure ( from memory T cells) and epitopes linked to SARS-CoV-2 only. This could possibly lead to a more comprehensive/foolproof “ immunity” test
Some infected people do not produce antibodies and do not test positive on a serological test. This might just be because they developed a quick T-cell response and cleared the virus quickly before antibodies could develop. They have memory T cells to show for it and are “ effectively” immune.

And, yes, this would be big news, but I don't think it terribly surprising. A lot of people have hypothesized this, including myself- it is nice to have some solid confirmation of it.

So what’s the main takeaway? Is it that it’s not quite as dangerous (relatively speaking) as we thought? That we are perhaps closer to herd immunity that we may have previously realized? Maybe a combo of the two?

If yes, then that’s obviously great! But I fear this will just be used as an excuse to engage is reckless behavior... or perhaps encourage riskier behavior.

At what point would you recommend re-commencing riskier behavior? (This is not tongue in cheek—I’m legitimately wondering)

That is easy.

You should probably be locked away from public until you die of old age. It is the only way to be safe. Also, you can catch COVID-19 over the internet.

This seems a bit of a stretch with a disease that isn't even one year old. 'thereby providing evidence for T-cell immunity upon infection'

Or, to change a single word - 'thereby providing evidence for T-cell response upon infection'

think immunologists use phrase" t cell immunity" = an immune response not necessarily meaning it confers effective immunity (protection) against the virus

And, also, they seem to find there are no abnormal deviations in immune response due to the heterologous immunity (that which comes from experience with other coronaviridae), which can happen in some cases I have read.

• 81 % of unexposed individuals in the study had nonetheless a T cell response to SARS-Cov2 epitopes consistent with cross reactivity from previous human coronaviruses ( HCoVs )
• Some patients after infection showed no antibody response but showed a T cell specific response
• A lower T cell response was associated with individuals with more severe COVID-19 symptoms.
This means:
1. A T cell response detection test might replace or supplement an antibody test , possibly catching more immune individuals than the standard serological test
2. some people may not develop antibodies possibly because they have a robust T cell sufficient to clear the virus very quickly.
It’s definitely plausible. An effective T cell response begins in the lymph node and can drain an antigen within 12 to 18 hours in some cases,
There’s a large cohort of asymptomatic people ( never symptomatic) who clear the virus quickly. In the very recent Nature paper on the Vo, Italy updated data, they found 40% asymptomatic and no infection in 234 children under 10 , a proportion of which lived in infected households.
This also matches the more severe disease progression in older people and the course of immuno senescence. The atrophy of the thymus begins in childhood in humans and results in the reduction of the production of naive T cells.

Your statement here seems key:

"The atrophy of the thymus begins in childhood in humans and results in the reduction of the production of naive T cells."

I admit to not knowing anything about the thymus gland, but a quick search turned up:

"A peculiar feature of the thymus is that it disappears as we get older. The thymus starts deteriorating after birth but the process speeds up after puberty and, by age 65, we are basically unable to make new T cells." (link:

So now it makes sense to me why age is such a crucial factor with SARS-CoV-2 - older folks can only amount an effective response against antigens they have seen in the past since such a response to a novel pathogen requires naive T cells to be present in sufficient number.

Knut Wittkowski was right all along?

We simply have nowhere near the length of time concerning this disease to state "possibly catching more immune individuals."

It is just as reasonable to assume it would catch people whose exposure to the virus was beneath the threshhold of infection, but who are not immune, though they may have some resistance. The word immune is being very casually used in connection with a disease that has not even been around for a full calendar year.

One can fervently hope this is so, but evidence simply does not exist of how much immunity one has over five years, whether after recovering from an infection or showing such an immune system response.

Further t-cell claims -

An awareness that many questions remain fully open - "Larger and more longitudinal studies must now be done on both T cells and antibodies to understand how long-lasting the immunity is and how these different components of COVID-19 immunity are related," says Marcus Buggert.

Studies which should be done as quickly as possible. Maybe a place for Fast Grants to step to the plate and help deliver some necessary data, useful in a number of directions.

My current, tentative model is that people who become infected develop SARS-CoV-2 T-cell responses. Some may be T-cell positive while testing negative for antibodies, because antibodies appear to wane in some patients quite rapidly. Some seroprevalence surveys may therefore be underestimating the number of people who have been infected, but it’s hard to know the extent to which this is the case.

Some also have pre-existing T-cell responses, perhaps due to cross-reactivity. This does not prevent infection, but it may result in milder (or even asymptomatic) illness. This explains why some people react worse than other people. Crucially, the epidemiologists should have already factored this into their models: they know that only a small proportion of people have severe illness.

Back in February, the epidemiologists were unable to factor asymptomatic spread into their models. Mainly because there was no accepted consensus it was even possible, much less actually happening.

Operation Warp Speed is relying exclusively on these newer technologies to finding an effective covid vaccine. In contrast, China is relying exclusively on the older technologies. One factor in favor of the newer technologies is that they are faster than the conventional technologies. One factor against the newer technologies is that they have never resulted in approved vaccines, much less vaccines with long track records. And that's the source of criticism of Operation Warp Speed: total reliance on an unproven technology. There. Now, consider what happens if the new technologies fail, while China produces an effective vaccine using conventional technologies. Do we go hat in hand to the Chinese.

I'm surprised at how little attention is given to this, the OWS approach to finding a vaccine vs. the Chinese approach. I suppose a reason is that, what, 1% of folks know about the different approaches, or what that means. The new approach to vaccines isn't all that new, but the new approach hasn't produced approved vaccines. What if OWS produces a vaccine that isn't approved. Will our friends here at MR attack the messenger, or attack OWS for taking a singular course for the development of a vaccine. I mean, Tabarrok has stressed again and again not to put all our eggs in one basket, to develop facilities for more than one vaccine in development. Yet, here we are, putting all our eggs in one basket.

You are totally wrong! China as a lot of others are looking at a variety of different vaccine technologies. They have both mRNA, DNA, and inactive viral vaccines under development.

Operation Warp Speed is not the only game in town and believe me I'm one of the major critics of it. I can only refer one to my Newsletter where I have been tracking all of this since mid-March. Not all of the vaccines in OWS are equivalent.

Totally wrong that OWS is putting all the eggs in one basket with an unproven technology (in the sense of never producing an approved vaccine), or totally wrong that China is relying on conventional, proven technology? Saying you are a "major critic" of OWS doesn't answer the question. I get it, scientists hedge about everything, even in the direction the sun sets, because science is complicated. But that doesn't excuse the failure to disclose the options being considered, the options being chosen, the options being rejected, and the risks that are taken as a result. "They have both mRNA, DNA, and inactive viral vaccines under development." Who are "they"? The Chinese? The martians?

Here is a list of major vaccine developments including a number of Recombinant protein vaccines which have been used for human vaccines.

Developing more traditional inactivated or attenuated vacines are also an art and with inactivated virus vacines you have the safety concerns of having to produce a large number of active viruses before inactivating them.

How was lunch in the PLA cafeteria today, “Thiago”?

I know neither Thiago nor PLA. I am Mr. Chalmers, a Florida highschool teacher.

Coincident with this, has anyone noticed how the tale of the "disastrous" and "catastrophic" approach to the virus in Sweden has completely fallen out of the news lately? I'll give you just one guess as to why.

I'm unclear whether you expect a Sweden-oriented answer, are soliciting a US-is-crap answer, or would welcome an MSM-is-appalling answer.

For the US I think an ancient usage applies: the USA are... When power lies with Governors and even Mayors there's little point discussing the Fedgov except to mourn the hapless job done by the CDC and FDA.

That the MSM is appalling is just an axiom.

As for the Swedes, I congratulate them for forming their own policy independent of the panic and fashions elsewhere. I also congratulate the Australian government whose key decision seems to have been to ignore the advice of their medical experts and close the borders.

MSM-is-appalling is kind of what I was going for. Sweden was all the rage for about 1 week - the one week during which it's daily death rate, which was falling at a slightly lower rate than the harder hit countries in Europe briefly ascended to be "the worst in Europe" (because it hadn't fallen quite as low as fast). When people stopped dying altogether, its a hushed "don't mention the Swedes." It'll mess with our narrative.

Frankly, I don't think the US has done bad at all. The virus will claim between 500 and 1,000 per million lives in a population, depending on demographics. It's just a question of when.

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