Self-Reported Use of COVID-19 Immunologic Test Results to Inform Decisions About Daily Activities and COVID-19 Vaccination (preprint)

Importance: Despite widespread use of clinical diagnostic tests to assess prior exposure to SARS-CoV-2, limited evidence exists regarding how test results affect patient behaviors and decision-making. Objective: To understand the rationale behind ordering diagnostic T-cell receptor (TCR) immunosequencing for assessment of prior SARS-CoV-2 infection and evaluate how test results affect patient behaviors, including day-to-day activities and decisions about vaccination. Design: Mandatory demographic information and clinical characteristics were collected for all individuals ordering T-DetectTM COVID. Study participants completed a one-time survey that included additional questions about demographics and clinical characteristics, relevant interactions with healthcare providers, reasons for ordering diagnostic TCR immunosequencing, and the utility of test results. Setting: US participants ordering T-Detect COVID between February 2021 and March 2022. Participants: Of the 806 individuals who underwent diagnostic TCR immunosequencing, provided informed consent, and were sent the email survey, 718 completed the survey (response rate, 89.1%). At the time of receiving the test report, 25.5% of participants had been vaccinated against COVID-19, 29.7% reported a previous COVID-19 infection, and 25.6% were immunocompromised. Main Outcome(s) and Measure(s): Patient demographics and clinical characteristics were reported using descriptive statistics. Additional analyses explored trends in reported data over time and evaluated reasons for ordering diagnostic TCR immunosequencing and behaviors among participant subgroups (vaccinated or unvaccinated individuals and those with positive or negative test results). Logistic regression analysis evaluated factors that increased the likelihood of post-test vaccination. Results: Study participants ordered diagnostic TCR immunosequencing to understand their health status (55.0%) and to inform decision-making about daily activities (43.6%) and vaccination (38.3%). Most participants (92.1%) ordered diagnostic TCR immunosequencing for themselves without consulting their physician. Testing negative for prior SARS-CoV-2 infection was associated with increased likelihood of subsequent COVID-19 vaccination (31.0% vs 6.9%; median time to vaccination, 17.0 days vs 47.5 days), which was confirmed by logistic regression analysis. Conclusions and Relevance: This report presents patient-reported clinical utility of a commercial COVID-19 assay based on an immune response readout. Our findings suggest that participants used diagnostic TCR immunosequencing results to inform decisions about daily activities and COVID-19 vaccination. Trial Registration: Not applicable.

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.

The ImmuneRACE Study: A Prospective Multicohort Study of Immune Response Action to COVID-19 Events with the ImmuneCODE™ Open Access Database (preprint)

Background: Adaptive Biotechnologies has built an immune medicine platform based on the sequencing of immune receptors (immunoglobulins, B-cell receptors [BCRs] and T-cell receptors [TCRs]) with myriad applications in health and disease. This broad platform technology can be used to assess the diversity of the cellular adaptive immune system and track disease-associated TCRs and BCRs during the course of infection. The SARS-CoV-2 virus is spreading rapidly throughout the world, causing significant morbidity and mortality. Researchers, governments, and biotechnology companies are mobilizing to develop and distribute diagnostic and therapeutic alternatives to try to curb this global pandemic. Methods: In collaboration with our partners LabCorp/Covance, Adaptive Biotechnologies has opened the ImmuneRACE study to prospectively collect samples from individuals who have been infected with SARS-CoV-2, who have recovered from SARS-CoV-2 infection, or who have been exposed to someone infected with SARS-CoV-2. Discussion: We believe that the information contained within the genetics of the adaptive immune response to SARS-CoV-2 can improve our understanding of the immunobiology of this devasting virus and may inform efforts to improve current diagnostic and therapeutic approaches. To facilitate scientific and clinical advancement in the fight against COVID-19, the TCR sequence data resulting from the primary aims of this study will be made publicly available to scientists and researchers across the globe, an effort made possible through a collaboration with Microsoft. Trial registration: ImmunoRACE is registered with the US National Institutes of Health and can be accessed at ClinicalTrials.gov (NCT04494893).

Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels (preprint)

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,015 samples (from 827 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 83.8% [95% CI = 77.6-89.4]; Day 8-14 = 92.4% [87.6-96.6]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 96.7% [93.0-99.2]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in vaccine development as well as clinical diagnostics and monitoring.

A large-scale database of T-cell receptor beta (TCRβ) sequences and binding associations from natural and synthetic exposure to SARS-CoV-2. (preprint)

We describe the establishment and current content of the ImmuneCODE™ database, which includes hundreds of millions of T-cell Receptor (TCR) sequences from over 1,400 subjects exposed to or infected with the SARS-CoV-2 virus, as well as over 135,000 high-confidence SARS-CoV-2-specific TCRs. This database is made freely available, and the data contained in it can be downloaded and analyzed online or offline to assist with the global efforts to understand the immune response to the SARS-CoV-2 virus and develop new interventions.