Differential kinetics of T cell and antibody responses delineate dominant T cell epitopes in long-term immunity after COVID-19 (preprint)

Long-term immunity to SARS-CoV-2 is crucial for the development of herd immunity and the aim of vaccination approaches. Reports on rapidly decreasing antibody titers question the efficacy of humoral immunity. The relevance of T cell memory after COVID-19 is yet unclear. Longitudinal analysis of SARS-CoV-2 immunity in convalescents up to six months post-infection revealed decreasing and stable spike and nucleocapsid antibody responses, respectively. In contrast, T cell responses remained robust and even increased in frequency and intensity. Single epitope mapping of T cell diversity over time identified ORF-independent, dominant T cell epitopes mediating long-term SARS-CoV-2 T cell responses and may be fundamental for vaccine design.

Differential Kinetics of T Cell and Antibody Responses Delineate Dominant T Cell Epitopes in Long-Term Immunity after COVID-19 (preprint)

Long-term immunity to SARS-CoV-2 is crucial for the development of herd immunity and the aim of vaccination approaches. Reports on rapidly decreasing antibody titers question the efficacy of humoral immunity. The relevance of T cell memory after COVID-19 is yet unclear. Longitudinal analysis of SARS-CoV-2 immunity in convalescents up to six months post-infection revealed decreasing and stable spike and nucleocapsid antibody responses, respectively. In contrast, T cell responses remained robust and even increased in frequency and intensity. Single epitope mapping of T cell diversity over time identified ORF-independent, dominant T cell epitopes mediating long-term SARS-CoV-2 T cell responses and may be fundamental for vaccine design.Funding: This work was supported by the Bundesministerium für Bildung und Forschung (BMBF, FKZ:01KI20130; J.W.), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Grant WA 4608/1-2; J.W.), the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy (Grant EXC2180-390900677; S.S., H.-G.R., H.R.S., J.W.), the German Cancer Consortium (DKTK; S.S., H.-G.R., H.R.S.), the Wilhelm Sander Stiftung (Grant 2016.177.2; J.W.), the José Carreras Leukämie-Stiftung (Grant DJCLS 05 R/2017; J.W.) and the Fortüne Program of the University of Tübingen (Fortüne number 2451-0-0 and 2581-0-0; J.W.). Conflict of Interest: H.-G.R. is shareholder of Immatics Biotechnologies GmbH and Curevac AG. A.N., T.B., H.-G.R., and J.S.W. hold patents on peptides described in this manuscript secured under the numbers 20 169 047.6 and 20 190 070.1. The other authors declare no competing interests.Ethical Approval: The study was approved by and performed according to the guidelines of the local ethics committees (179/2020/BO2).

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

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.