This is a preprint. Preprints are preliminary reports that have not undergone peer review. They should not be considered conclusive, used to inform clinical practice, or referenced by the media as validated information.
Research Article
SARS-CoV-2 T-cell epitopes define heterologous and COVID-19-induced T-cell recognition
Juliane S. Walz
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
Corresponding Author
ORCiD: https://orcid.org/0000-0001-6404-7391
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Declarations:
View the published version here.
View Research Highlight
Research Highlight
created by Research Square
SARS-CoV-2, the virus causing COVID-19, has dramatically altered life around the globe. For antiviral therapeutics like vaccines to work, scientists need to know which areas of the virus - or epitopes - can activate immune cells called T cells. The authors of this study used computer algorithms to predict which epitopes of SARS-CoV-2 could activate T cells. To confirm those predictions, they measured how T cells responded using blood samples from two groups of people: 180 individuals previously infected with SARS-CoV-2 and 185 individuals not exposed to the virus. The team discovered that some epitopes were specific to SARS-CoV-2, while others were cross-reactive—they were similar enough to epitopes on common-cold-causing viruses to prompt a T-cell response. In fact, 81% of unexposed individuals had some T-cell response to these epitopes. While this suggests at least some built-in immune protection from SARS-CoV-2, T-cell responses in previously infected people were much more robust than those in unexposed individuals. Individuals with a broader T-cell response to viral epitopes reported less-severe COVID-19 symptoms, suggesting that people with some T-cell recognition of SARS-CoV-2 prior to infection may exhibit less severe illness. Additional studies comparing the same subjects before and after infection are needed to understand how T-cell cross-reactivity relates to immunity and symptom severity. Nevertheless, this study suggests that promoting T-cell responses to SARS-CoV-2 may be important for designing effective therapeutic and preventive measures.
View Research Highlight
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.
Keywords
SARS-CoV-2, COVID-19, T-cell epitopes, HLA peptides, vaccine design, T-cells, immunity
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementaryTables.pdf(2020-06-17 00:23:30)
- SupplementaryFigures.pdf(2020-06-17 00:23:31)
- SupplementaryData1.pdf(2020-06-17 00:23:31)
- ManuscriptNeldeetalwithExtendedData.pdf(2020-06-17 00:23:31)
Juan Arkani
ORCiDcommented on 29 June, 2020
The study found by measuring recognition of the epitopes of SARS-Cov-2 that diversification had been lower in patients with more severe symptoms ”Rather, diversity of T-cell responses in terms of recognition rate of SARS-CoV-2 T-cell epitopes was decreased in patients with more severe COVID-19 symptoms ”. However, these patients had higher levels of antibodies! The question here is whether various previous epitopes "similarities to the four seasonal common cold human coronaviruses (HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-HKU1)" are responsible for a mechanism that stimulates (specifically?) and induces how T-cells react. In other words whether the presence of previous cross-reactive epitopes more or less (specifically?) dictates in which direction the cellular immune response goes and also affects the humoral branch, depending on which cell line dominates, namely the CD8 cell line or the CD4 cell line, and if the CD4 cell line goes in the direction of Th1 or Th2. In this latter case dominance of the Th2 direction with antibody production may explain the observed positive correlation between the severity of symptoms and the development of antibodies as mentioned in the study and with reference also to another study with hospitalized patients. Moreover there may be individuals who are at higher risk of severe course of COVID-19 not only on the basis of other previously identified risk factors such as age and comorbidities, but also an "immunologically high risk group" that is independent of other risk factors but is nevertheless affected by them.
Paul Taylor
commented on 01 July, 2020
As a synthetic organic chemist reading your note I was struck by the last paragraph of your discussion. It may be that I am unfamiliar with the way immunologists deliver information but are you saying that the stage after identifying the two epitopes is to develop a vaccine that instead of prompting the body to produce antibodies to attack the virus you intend to use T cells to do the attacking. I ask because this T cell treatment seems to be using just that approach. https://uk.reuters.com/article/uk-health-coronavirus-britain-tcell/scottish-firm-to-trial-t-cells-as-possible-covid-19-treatment-idUKKBN24135C If so presumably these T cells might provide ongoing protection against future coronaviruses. I that your proposed approach?
View 1 reply
Martin Feyerabend
commented on 17 August, 2020
Some people interpret your findings as a hint that herd immunity might be given in 80% of the population or at least achievable by simple well known health care measures. Vaccination procedures for people under 60 Y might be unnecessary?
View 1 reply
Gugelmugel Mugelgugel
replied on 18 September, 2020
Da gibt es keine andere Interpretation, werter Kollege
Udo Schlenz
commented on 25 November, 2020
Ich möchte an die Frage von @Martin Feyerabend v. 17.August erinnern mit Bitte ans Autorenteam um Beantwortung. Es gibt ja auch kontrastierende Ideen, die die Möglichkeit einer Verschlechterung eines Cov2-Verlaufs durch preexistente T-Zellen Reaktiviät vs gemeiner Human-Corona-Viren (HCV) beinhalten. Zur Klärung solcher Fragestellung sollten empirische Daten hilfreich sein. Man könnte zu irgendeiner Kohorte von bisher Nichtinfizierten, für die historische Daten betr HCV vorliegen, die aktuellen Raten betr Infektion/Hospitalisierung etc mit Cov2 ermitteln. Zb die Kohorte der hier in Studie verwendeten Nichtexponierten ! Alternative Ideen geeignet zu messen, gäbe es natürlich. Etwa das Checken auf HCV-reakt. T-Zellen von bisher nicht Cov2-pos. detektierten Haushaltsmitglieder bei mindest 2 bereits Infizierten im selben Haushalt.
View 1 reply
Juliane Walz
replied on 25 November, 2020
Sehr geehrter Herr Schlenz, danke für Ihren Kommentar. An solchen prospektiven Analysen wie von Ihnen vorgeschlagen arbeiten wir aktuell und beobachten eine Kohorte an Probanden von denen wir die Information zu kreuzreaktiven T-Zellen haben auf eine Infektion mit SARS-CoV-2 und den Krankheitsverlauf von COVID-19. Solche Projekte werden zudem von weiteren Arbeitsgruppen weltweit durchgeführt, sodass wir hier hoffentlich bald neue Informationen zur Rolle kreuzreaktiver T-Zellen erhalten.
1 comment flagged for moderation
If you posted a comment and think it was mistakenly removed, please contact customer support at [email protected].
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 16 Jun, 2020
Published
On 30 Sep, 2020
Community comments: 11
Metrics
Comments: 11
PDF Downloads: ...
HTML Views: ...
Learn more about our company.
This is a preprint. It has not completed peer review.
Research Article
SARS-CoV-2 T-cell epitopes define heterologous and COVID-19-induced T-cell recognition
Juliane S. Walz
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
Corresponding Author
ORCiD: https://orcid.org/0000-0001-6404-7391
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 16 Jun, 2020
Published
On 30 Sep, 2020
Community comments: 11
Metrics
Comments: 11
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Declarations:
View the published version here.
View Research Highlight
Research Highlight
created by Research Square
SARS-CoV-2, the virus causing COVID-19, has dramatically altered life around the globe. For antiviral therapeutics like vaccines to work, scientists need to know which areas of the virus - or epitopes - can activate immune cells called T cells. The authors of this study used computer algorithms to predict which epitopes of SARS-CoV-2 could activate T cells. To confirm those predictions, they measured how T cells responded using blood samples from two groups of people: 180 individuals previously infected with SARS-CoV-2 and 185 individuals not exposed to the virus. The team discovered that some epitopes were specific to SARS-CoV-2, while others were cross-reactive—they were similar enough to epitopes on common-cold-causing viruses to prompt a T-cell response. In fact, 81% of unexposed individuals had some T-cell response to these epitopes. While this suggests at least some built-in immune protection from SARS-CoV-2, T-cell responses in previously infected people were much more robust than those in unexposed individuals. Individuals with a broader T-cell response to viral epitopes reported less-severe COVID-19 symptoms, suggesting that people with some T-cell recognition of SARS-CoV-2 prior to infection may exhibit less severe illness. Additional studies comparing the same subjects before and after infection are needed to understand how T-cell cross-reactivity relates to immunity and symptom severity. Nevertheless, this study suggests that promoting T-cell responses to SARS-CoV-2 may be important for designing effective therapeutic and preventive measures.
View Research Highlight
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.
Figure 1
Figure 2
Figure 3
Figure 4
Juan Arkani
ORCiDcommented on 29 June, 2020
The study found by measuring recognition of the epitopes of SARS-Cov-2 that diversification had been lower in patients with more severe symptoms ”Rather, diversity of T-cell responses in terms of recognition rate of SARS-CoV-2 T-cell epitopes was decreased in patients with more severe COVID-19 symptoms ”. However, these patients had higher levels of antibodies! The question here is whether various previous epitopes "similarities to the four seasonal common cold human coronaviruses (HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-HKU1)" are responsible for a mechanism that stimulates (specifically?) and induces how T-cells react. In other words whether the presence of previous cross-reactive epitopes more or less (specifically?) dictates in which direction the cellular immune response goes and also affects the humoral branch, depending on which cell line dominates, namely the CD8 cell line or the CD4 cell line, and if the CD4 cell line goes in the direction of Th1 or Th2. In this latter case dominance of the Th2 direction with antibody production may explain the observed positive correlation between the severity of symptoms and the development of antibodies as mentioned in the study and with reference also to another study with hospitalized patients. Moreover there may be individuals who are at higher risk of severe course of COVID-19 not only on the basis of other previously identified risk factors such as age and comorbidities, but also an "immunologically high risk group" that is independent of other risk factors but is nevertheless affected by them.
Paul Taylor
commented on 01 July, 2020
As a synthetic organic chemist reading your note I was struck by the last paragraph of your discussion. It may be that I am unfamiliar with the way immunologists deliver information but are you saying that the stage after identifying the two epitopes is to develop a vaccine that instead of prompting the body to produce antibodies to attack the virus you intend to use T cells to do the attacking. I ask because this T cell treatment seems to be using just that approach. https://uk.reuters.com/article/uk-health-coronavirus-britain-tcell/scottish-firm-to-trial-t-cells-as-possible-covid-19-treatment-idUKKBN24135C If so presumably these T cells might provide ongoing protection against future coronaviruses. I that your proposed approach?
View 1 reply
Juliane Walz
replied on 03 July, 2020
Thank you very much for your interest in our study. Indeed we are currently planning a peptide vaccination study based on our preclinical work. In contrast to the T-cell transfer pursued by the scottish firm you mentioned our approach aims to induce SARS-CoV-2 T-cell responses in vivo applying the identified T-cell epitopes as a peptide vaccine.
View 3 replies
Paul Taylor
replied on 03 July, 2020
Thanks for the reply, I find this approach an truly exciting one and hope it is successful, If there were a choice of vaccines in the battle against Covid-19 it would be my vaccine of choice. The potential of this approach is of course that the T cells generated to fight the current pandemic might well offer a cross ‘protection’ against future coronaviral epidemics. This will give any vaccine developed following this approach a unique advantage over any other vaccine simply inducing antibodies. I have a website that reviews coronavirus developments, https:coronaviruswales.uk I’ll post an article there to help advance your profile and look forward to the full paper in due course. Great research thank you.
View 1 reply
Payton Harris
replied on 20 July, 2020
Just for your information. As Juliane said, in order to get long lasting immunity to a virus or bacteria, a protein must be used. If you use a sugar or polysaccaride, it activates the immune system in a T cell independent manor. This bypasses T cells and gets B cells to produce antibodies for a short period of time. You see this in vaccines that you need boosters for such as the Tdap vaccine for tetanus, diphtheria and pertussis. Vaccines that use proteins are able to be processed and stimulate T cells to produce long lasting immunity that can reactivate B cells , in some cases life long. Examples of this are the many of the "live vaccines" such as MMR, and Varicella. That is why you do not need to get boosters for them and are typically conferred with lifelong immunity.
Itamar Barbosa
replied on 21 July, 2020
Very interesting and attractive approach. I am a nurse in US and interested on the fact that most current front runners working on vaccines such as Moderna and Innovio lack improving of T cells. In your approach would it be necessary to add a coadjuvante agent to current clinical vaccine human trials to address this “ deficiency” in order to produce a vaccine that last longer?
Salomon Jakubowicz
replied on 22 August, 2020
Do any of the leading vaccine aim to elicit T cells? Thanks a lot for your super important research.
Martin Feyerabend
commented on 17 August, 2020
Some people interpret your findings as a hint that herd immunity might be given in 80% of the population or at least achievable by simple well known health care measures. Vaccination procedures for people under 60 Y might be unnecessary?
View 1 reply
Gugelmugel Mugelgugel
replied on 18 September, 2020
Da gibt es keine andere Interpretation, werter Kollege
Udo Schlenz
commented on 25 November, 2020
Ich möchte an die Frage von @Martin Feyerabend v. 17.August erinnern mit Bitte ans Autorenteam um Beantwortung. Es gibt ja auch kontrastierende Ideen, die die Möglichkeit einer Verschlechterung eines Cov2-Verlaufs durch preexistente T-Zellen Reaktiviät vs gemeiner Human-Corona-Viren (HCV) beinhalten. Zur Klärung solcher Fragestellung sollten empirische Daten hilfreich sein. Man könnte zu irgendeiner Kohorte von bisher Nichtinfizierten, für die historische Daten betr HCV vorliegen, die aktuellen Raten betr Infektion/Hospitalisierung etc mit Cov2 ermitteln. Zb die Kohorte der hier in Studie verwendeten Nichtexponierten ! Alternative Ideen geeignet zu messen, gäbe es natürlich. Etwa das Checken auf HCV-reakt. T-Zellen von bisher nicht Cov2-pos. detektierten Haushaltsmitglieder bei mindest 2 bereits Infizierten im selben Haushalt.
View 1 reply
Juliane Walz
replied on 25 November, 2020
Sehr geehrter Herr Schlenz, danke für Ihren Kommentar. An solchen prospektiven Analysen wie von Ihnen vorgeschlagen arbeiten wir aktuell und beobachten eine Kohorte an Probanden von denen wir die Information zu kreuzreaktiven T-Zellen haben auf eine Infektion mit SARS-CoV-2 und den Krankheitsverlauf von COVID-19. Solche Projekte werden zudem von weiteren Arbeitsgruppen weltweit durchgeführt, sodass wir hier hoffentlich bald neue Informationen zur Rolle kreuzreaktiver T-Zellen erhalten.
Juliane Walz
replied on 03 July, 2020
Thank you very much for your interest in our study. Indeed we are currently planning a peptide vaccination study based on our preclinical work. In contrast to the T-cell transfer pursued by the scottish firm you mentioned our approach aims to induce SARS-CoV-2 T-cell responses in vivo applying the identified T-cell epitopes as a peptide vaccine.
View 3 replies
Paul Taylor
replied on 03 July, 2020
Thanks for the reply, I find this approach an truly exciting one and hope it is successful, If there were a choice of vaccines in the battle against Covid-19 it would be my vaccine of choice. The potential of this approach is of course that the T cells generated to fight the current pandemic might well offer a cross ‘protection’ against future coronaviral epidemics. This will give any vaccine developed following this approach a unique advantage over any other vaccine simply inducing antibodies. I have a website that reviews coronavirus developments, https:coronaviruswales.uk I’ll post an article there to help advance your profile and look forward to the full paper in due course. Great research thank you.
View 1 reply
Payton Harris
replied on 20 July, 2020
Just for your information. As Juliane said, in order to get long lasting immunity to a virus or bacteria, a protein must be used. If you use a sugar or polysaccaride, it activates the immune system in a T cell independent manor. This bypasses T cells and gets B cells to produce antibodies for a short period of time. You see this in vaccines that you need boosters for such as the Tdap vaccine for tetanus, diphtheria and pertussis. Vaccines that use proteins are able to be processed and stimulate T cells to produce long lasting immunity that can reactivate B cells , in some cases life long. Examples of this are the many of the "live vaccines" such as MMR, and Varicella. That is why you do not need to get boosters for them and are typically conferred with lifelong immunity.
Itamar Barbosa
replied on 21 July, 2020
Very interesting and attractive approach. I am a nurse in US and interested on the fact that most current front runners working on vaccines such as Moderna and Innovio lack improving of T cells. In your approach would it be necessary to add a coadjuvante agent to current clinical vaccine human trials to address this “ deficiency” in order to produce a vaccine that last longer?
Salomon Jakubowicz
replied on 22 August, 2020
Do any of the leading vaccine aim to elicit T cells? Thanks a lot for your super important research.