Detection of virus-specific and cross-reactive T-cell responses to coronaviruses

Detection of SARS-CoV-2-specific immune responses relies on antibody testing. However, asymptomatic and mild cases do not always develop antibodies and specific antibodies may not be long-lived. At the same time, virus-specific T-cell responses appear long-lived, detectable after asymptomatic infection, and after recovery from disease. Therefore, detection of SARS-CoV-2-specific T-cells could be a valuable marker for exposure to SARS-CoV-2. Here, we propose to develop of a diagnostic test to measure SARS-CoV-2 exposure or vaccine efficacy.

SARS-CoV-2 is related to a number of seasonal coronaviruses endemic in humans that usually cause “common cold” symptoms (HCoVs). Several studies have shown that with the current technology, SARS-CoV-2-specific T-cells are also detected in individuals never exposed to SARS-CoV-2. This likely reflects the presence of so-called cross-reactive T-cells, i.e. T-cells induced by HCoVs that cross-recognize SARS-CoV-2. To study SARS-CoV-2-specific immunity on the individual and population level, it is of paramount importance that we are able to discriminate between T-cell responses that recognize SARS-CoV-2, HCoVs or both.

To this end, we will generate unique discriminatory peptide pools and validate these in samples obtained from acute and convalescent COVID-19 patients, and unexposed control subjects. We will also study the longevity of T-cell responses and follow a well-defined cohort for re-infections. The outcomes of this project will provide a fundamental understanding of T-cell responses to coronaviruses and contribute to answering questions about the role of coronavirus-specific T-cells in COVID-19. On the longer run, methods developed here potentially lead to a T-cell assay that could be employed as a diagnostic test to detect SARS-CoV-2 exposure, or to determine the ability of vaccines developed in the near future to induce T-cell responses.

During the course of the project, ethical permits were acquired to study T-cell responses in response to infection or vaccination in humans. We in silico designed peptide pools required to measure SARS-CoV-2-, SARS2-variant-, MERS-CoV, and HCoV-specific T-cell responses, and generated these peptide pools. After showing that these peptide pools were non-toxic and able to activate T-cells in control samples, we tested them in established cohorts of SARS-CoV-2 infected and COVID-19 vaccinated individuals. Our in-house designed peptide pools performed in a more specific manner than commercially available assays, and were able to detect T-cell responses at a higher sensitivity. We showed that T-cell responses can be detected up to 6 months after exposure, but were not able to extend this period due to recurrent infections and booster vaccinations. Although not described as a deliverable due to the changing landscape of COVID-19, we showed that these peptide pools can be used to measure vaccine immunogenicity.