Systems and Longitudinal Analysis Reveals Early-Stage and Highly Coordinated Immune Responses in Mild COVID-19 Patients (preprint)

While immunopathology has been widely studied in severe COVID-19 patients, immunoprotective factors in non-hospitalized patients have remained largely elusive. We systematically analyzed 484 peripheral immune cell signatures, various serological parameters and TCR repertoire in a longitudinal cohort of 63 mild and 15 hospitalized patients versus 14 asymptomatic and 26 control individuals. Within three days following PCR diagnosis, we observed coordinated responses of CD4 and CD8 T cells, various antigen presenting cells and antibody-secreting cells in mild, but not hospitalized COVID-19 patients. This early-stage SARS-CoV-2-specific response was predominantly characterized by substantially expanded clonotypes of CD4 and less of CD8 T cells. The early-stage responses of T cells and dendritic cells were highly predictive for later seroconversion and protective antibody levels after three weeks in mild non-hospitalized, but not in hospitalized patients. Our systemic analysis reveals the first full picture and early-stage trajectory of highly-coordinated immune responses in mild COVID-19 patients.Funding: The Predi-COVID study is supported by the Luxembourg National Research Fund (FNR) (Predi-COVID, 14716273) and the André Losch Fondation. We also highly appreciate the expert support of the IBBL processing and biorepository teams. F.Q.H. was partially supported by FNR CORE programme grant (CORE/14/BM/8231540/GeDES), FNR AFR- RIKEN bilateral programme (TregBAR, 11228353, F.Q.H. and M.O.) and PRIDE programme grants (PRIDE/11012546/NEXTIMMUNE and PRIDE/10907093/CRITICS). C.H. was partially supported by the FNR fast-track call COVID-19/2020-1/14703957/COV-Immun.Declaration of Interests: The authors declare that they have no conflict of interest.Ethics Approval Statement: All collections were performed with approval from relevant ethic organizations. Informed consent was obtained from each participant prior to collection. The blood sampling was performed by nurses from Clinical and Epidemiological Investigation Centre (CIEC) of LIH.

Clinical Validation of a Novel T-cell Receptor Sequencing Assay for Identification of Recent or Prior SARS-CoV-2 Infection (preprint)

ABSTRACT Background While diagnostic, therapeutic, and vaccine development in the COVID-19 pandemic has proceeded at unprecedented speed and scale, critical gaps remain in our understanding of the immune response to SARS-CoV-2. Current diagnostic strategies, including serology, have numerous limitations in addressing these gaps. Here we describe clinical performance of T- Detect™ COVID, the first reported assay to determine recent or prior SARS-CoV-2 infection based on T-cell receptor (TCR) sequencing and immune repertoire profiling from whole blood samples. Methods Methods: for high-throughput immunosequencing of the TCRβ gene from blood specimens have been described 1 . We developed a statistical classifier showing high specificity for identifying prior SARS-CoV-2 infection 2 , utilizing >4,000 SARS-CoV-2-associated TCR sequences from 784 cases and 2,447 controls across 5 independent cohorts. The T-Detect COVID Assay comprises immunosequencing and classifier application to yield a qualitative positive or negative result. Several retrospective and prospective cohorts were enrolled to assess assay performance including primary and secondary Positive Percent Agreement (PPA; N=205, N=77); primary and secondary Negative Percent Agreement (NPA; N=87, N=79); PPA compared to serology (N=55); and pathogen cross-reactivity (N=38). Results T-Detect COVID demonstrated high PPA in subjects with prior PCR-confirmed SARS-CoV-2 infection (97.1% 15+ days from diagnosis; 94.5% 15+ days from symptom onset), high NPA (∼100%) in presumed or confirmed SARS-CoV-2 negative cases, equivalent or higher PPA than two commercial EUA serology tests, and no evidence of pathogen cross-reactivity. Conclusion T-Detect COVID is a novel T-cell immunosequencing assay demonstrating high clinical performance to identify recent or prior SARS-CoV-2 infection from standard blood samples. This assay can provide critical insights on the SARS-CoV-2 immune response, with potential implications for clinical management, risk stratification, surveillance, assessing protective immunity, and understanding long-term sequelae.