Diagnosis and Tracking of SARS-CoV-2 Infection By T-Cell Receptor Sequencing

Abstract

Measuring the adaptive immune response after SARS-CoV-2 infection may improve our understanding of COVID-19 exposure and potential future protection or immunity. We analyzed T-cell and antibody signatures in a large population study of over 2,200 individuals from the municipality of Vo’, Italy, including 70 PCR-confirmed SARS-CoV-2 cases (24 asymptomatic, 37 symptomatic, 9 hospitalized). Blood samples taken 60 days after PCR diagnosis demonstrated 97% (68/70) of the latter subjects had a positive T-cell test result, higher than an antibody serology assay (77%; 54/70 of subjects) performed on the same samples. The depth and breadth of the T-cell response was associated with disease severity, with symptomatic and hospitalized COVID-19 cases having significantly higher response than asymptomatic cases. In contrast, antibody levels at this convalescent time point were less informative as they did not correlate with disease severity. 45 additional suspected infections were identified based on T-cell response from the 2,220 subjects without confirmatory PCR tests. Among these, notably, subjects who reported symptoms or had household exposure to a PCR-confirmed infection demonstrated a higher T-cell test positive rate. Taken together, these results establish that T cells are a sensitive, reliable and persistent measure of past SARS-CoV-2 infection.

T-cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibody titers and disease severity

“…These associations are independent of the number of unique T-cell rearrangements, which was included in the multi-variable regression. The association between magnitude of the T-cell response and clinical indicators of disease severity is consistent with other reports showing higher T-cell responses in symptomatic versus asymptomatic individuals that can persist months after infection (3, 21). We hypothesize that increased viral load, longer viral persistence, and/or higher levels of immune activation during acute SARS-CoV-2 infection may in part underlie the association between more severe COVID-19 illness and greater recruitment and long-term durability of the T-cell response.…”

“…Based on identification of public SARS-CoV-2–specific T-cell signatures shared across individuals, a classifier was developed to diagnose recent and past SARS-CoV-2 infection (17) in previously-confirmed RT-PCR-positive cases that has been validated in several independent data sets (18, 21). Optimization and application of this TCR classifier (further described in Methods) as a test for past SARS-CoV-2 infection yielded a sensitivity of 88.8% across all samples and timepoints, with a specificity of 99.8% in a control set of 1,657 pre-pandemic samples sequenced prior to 2020 (Figure 3A; Supplemental Table 2).…”

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

“…This performance was consistent across several retrospective and prospective cohorts and longitudinal sampling timeframes. Utilizing this approach in a real-world setting, we have shown previously that robust T-cell signals are persistent at least 6 months after primary SARS-CoV-2 infection 42 , consistent with other reports 44 . In the SARS-CoV-1 pandemic, detectable virus-specific T-cell responses were observed in recovered individuals up to 17 years later 21 .…”

“…Here we describe the implementation and extensive clinical validation of T-Detect™ COVID, a novel high-throughput assay to determine recent or prior SARS-CoV-2 infection based on T-cell receptor gene sequencing and subsequent repertoire profiling from whole blood samples, following US Food and Drug Administration guidance “ Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised) May2020.” We demonstrate high positive and negative percent agreement of this assay to identify or exclude prior SARS-CoV-2 infection in PCR-confirmed SARS-CoV-2 cases across several cohorts and longitudinal timepoints. We also show that the assay has equivalent or better performance than commercially-available EUA antibody tests at all timepoints evaluated 42 , and lacks cross-reactivity to several viral and/or respiratory pathogens.…”

The Future of Blood Testing Is the Immunome

“…Similar results have been demonstrated in viral infections as diverse as dengue and SARS-CoV-2 ( 21 – 28 ). Noteworthy in this regard is the current effort to discern a T cell fingerprint for SARS-CoV-2 exposure, immune status and possibly even immunopathology in the ImmuneCODE project, a collaboration between Adaptive Biotechnologies and Microsoft, which leverages a rapidly growing and publicly accessible dataset of over 1,400 TR immunomes from individuals who were exposed to SARS-CoV-2 ( 28 , 29 ). Patterns have been reported in a host of autoimmune diseases such as lupus ( 30 – 33 ), and antibodies and TRs against neoantigens have been reported across solid tumors and in specific cancers such as melanoma ( 34 ).…”