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129th ASEE Annual Conference and Exposition: Excellence Through Diversity, ASEE 2022 ; 2022.
Article in English | Scopus | ID: covidwho-2045796
Open Forum Infectious Diseases ; 8(SUPPL 1):S77, 2021.
Article in English | EMBASE | ID: covidwho-1746783


Background. T cells are central to the early identification and clearance of viral infections and support antibody generation by B cells, making them desirable for assessing the immune response to SARS-CoV-2 infection and vaccines. We combined 2 high-throughput immune profiling methods to create a quantitative picture of the SARS-CoV-2 T-cell response that is highly sensitive, durable, diagnostic, and discriminatory between natural infection and vaccination. Methods. We deeply characterized 116 convalescent COVID-19 subjects by experimentally mapping CD8 and CD4 T-cell responses via antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I and 284 class II viral peptides. We also performed T-cell receptor (TCR) repertoire sequencing on 1815 samples from 1521 PCR-confirmed SARS-CoV-2 cases and 3500 controls to identify shared public TCRs from SARS-CoV-2-associated CD8 and CD4 T cells. Combining these approaches with additional samples from vaccinated individuals, we characterized the response to natural infection as well as vaccination by separating responses to spike protein from other viral targets. Results. We find that T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the SARS-CoV-2 T-cell response peaks about 1-2 weeks after infection and is detectable at least several months after recovery. Applying these data, we trained a classifier to diagnose past SARS-CoV-2 infection based solely on TCR sequencing from blood samples and observed, at 99.8% specificity, high sensitivity soon after diagnosis (Day 3-7 = 85.1%;Day 8-14 = 94.8%) that persists after recovery (Day 29+/convalescent = 95.4%). Finally, by evaluating TCRs binding epitopes targeting all non-spike SARS-CoV-2 proteins, we were able to separate natural infection from vaccination with > 99% specificity. Conclusion. TCR repertoire sequencing from whole blood reliably measures the adaptive immune response to SARS-CoV-2 soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points, and distinguishes post-infection vs. vaccine immune responses with high specificity. This approach to characterizing the cellular immune response has applications in clinical diagnostics as well as vaccine development and monitoring.

Open Forum Infectious Diseases ; 8(SUPPL 1):S87, 2021.
Article in English | EMBASE | ID: covidwho-1746780


Background. Our understanding of the SARS-CoV-2 immune response has critical gaps that are inadequately addressed with available tools. We report the clinical performance of T-Detect COVID, the first T-cell assay to identify prior SARS-CoV-2 infection using T-cell receptor (TCR) sequencing and repertoire profiling from whole blood samples. Methods. The T-Detect COVID assay combines high-throughput immunosequencing of the TCRß gene from blood samples with a statistical classifier demonstrating 99.8% specificity for identifying prior SARS-CoV-2 infection. The assay was employed in several retrospective and prospective cohorts to assess primary and secondary Positive Percent Agreement (PPA) with SARS-CoV-2 RT-PCR (N=205;N=77);primary and secondary Negative Percent Agreement (NPA;N=87;N=79);PPA compared to SARS-CoV-2 serology (N=55);and pathogen cross-reactivity (N=38). The real-world performance of the test was also evaluated in a retrospective review of test ordering (N=69) at a single primary care clinic in Park City, Utah. Results. In validation studies, T-Detect COVID demonstrated high PPA (97.1% ≥15 days from diagnosis) in subjects with prior PCR-confirmed SARSCoV-2 infection;high NPA (~100%) in SARS-CoV-2 negative cases;equivalent or higher PPA with RT-PCR compared to two commercial EUA antibody tests;and no evidence of pathogen cross-reactivity. Review of assay use in a single clinic showed 100% PPA with RT-PCR in individuals with past confirmed SARS-CoV-2 vs. 85.7% for antibody testing, 100% agreement with positive antibody results, and positive results in 2/4 convalescent subjects with seroreversion to a negative antibody. In addition, 12/69 (17.3%) individuals with absent or negative RT-PCR tested positive by T-Detect COVID, nearly all of whom had compatible symptoms and/or exposure. TCR positivity was observed up to 12+ months (median 118 days) from the date of positive RT-PCR. Conclusion. A T-cell immunosequencing assay shows high clinical performance for identifying past SARS-CoV-2 infection from whole blood samples. This assay can provide additional insights on the SARS-CoV-2 immune response, with practical implications for clinical management, risk stratification, surveillance, assessing vaccine immunity, and understanding long-term sequelae.

Stroke ; 52(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1234356


Introduction: While coronavirus disease 2019 (COVID-19) has been associated with acute ischemic stroke (AIS), the causal relationship has yet to be elucidated. Factors that likely confer increased stroke risk are COVID-19-associated coagulopathy and hyperinflammatory response. Studying clinical features of patients with otherwise undetermined cause of AIS could help better define COVID-19-associated stroke. Methods: We performed a multicenter cross-sectional study of consecutive patients presenting with AIS and COVID-19 to one of two large healthcare systems in New York City during the local COVID- 19 surge from March 1, 2020 to May 31, 2020. In-hospital stroke cases were excluded. We compared demographic and clinical features of patients with COVID-19 and a cryptogenic AIS subtype to patients with COVID-19 and a determined subtype. Baseline characteristics and clinical variables were compared using chi-squared and Fisher exact tests. Results: A total of 62 patients with AIS and COVID-19 at the time of hospital arrival were identified. Of these, 30 were classified as having a cryptogenic subtype (80% after complete diagnotics evaluation), and 32 had an identifiable stroke mechanism. Patients with cryptogenic AIS were significantly younger (p=0.011) and less likely to have co-morbid hypertension (p=0.019), coronary artery disease (p=0.024), heart failure (p=0.039), atrial fibrillation (<0.0001), and prior stroke or TIA (p=0.033) compared to those with defined mechanisms. Further, d-dimer, but not C-reactive protein, was significantly higher in patients with cryptogenic stroke compared to those with defined causes (p=0.009). Conclusion: Patients with AIS in the setting of COVID-19 and no other determined stroke mechanism were younger, less likely to have classic risk factors, and had higher d-dimer levels when compared to those with a determined mechanism. Further study of COVID-19-associated hypercoagulability as a mechanism of stroke is warranted.