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1.
Clin Infect Dis ; 2022 Aug 12.
Article in English | MEDLINE | ID: covidwho-1992160

ABSTRACT

BACKGROUND: The burden and duration of persistent symptoms after non-severe COVID-19 remains uncertain. This study aimed to assess post-infection symptom trajectories in home-isolated COVID-19 cases compared to age- and time-period matched seronegative controls, and investigate immunological correlates of long COVID. METHODS: A prospective case-control study conducted between February 28th and April 4th 2020 included home-isolated COVID-19 cases followed for 12 (n = 233) to 18 (n = 149) months, and 189 age-matched SARS-CoV-2 naive controls. We collected clinical data at baseline, 6, 12 and 18 months post-infection, and blood samples at 2, 4, 6 and 12 months for analysis of SARS-CoV-2 specific humoral and cellular responses. RESULTS: Overall, 46% (108/233) had persisting symptoms 12 months after COVID-19. Compared to controls, adult cases had a high risk of fatigue (27% excess risk, gender and comorbidity adjusted odds ratio [aOR] 5.86, 95% confidence interval [CI]3.27-10.5), memory problems (21% excess risk, aOR 7.42, CI 3.51-15.67), concentration problems (20% excess risk, aOR 8.88, CI 3.88-20.35), and dyspnea (10% excess risk, aOR 2.66, CI 1.22-5.79). The prevalence of memory problems increased overall from 6 to 18 months (excess risk 11.5%, CI 1.5, 21.5, p = 0.024) and among women (excess risk 18.7%, CI 4.4, 32.9, p = 0.010). Longitudinal spike IgG was significantly associated with dyspnea at 12 months. The spike-specific clonal CD4 + TCRß depth was significantly associated with both dyspnea and number of symptoms at 12 months. CONCLUSIONS: This study documents a high burden of persisting symptoms after mild COVID-19, and suggest that infection induced SARS-CoV-2 specific immune responses may influence long-term symptoms.

4.
Front Immunol ; 13: 880190, 2022.
Article in English | MEDLINE | ID: covidwho-1809409

ABSTRACT

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vß gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.


Subject(s)
COVID-19 , Inflammatory Bowel Diseases , 2019-nCoV Vaccine mRNA-1273 , Ad26COVS1 , BNT162 Vaccine , COVID-19 Vaccines , Humans , Immunity, Humoral , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2 , Vaccines, Synthetic , mRNA Vaccines
5.
JCI Insight ; 7(10)2022 05 23.
Article in English | MEDLINE | ID: covidwho-1794308

ABSTRACT

BACKGROUNDMeasuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T cell responses, but these responses vary with disease severity and individual characteristics.METHODSA T cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T cell testing was assessed and compared with serologic testing.RESULTSSARS-CoV-2-specific T cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T cell testing was most apparent in recovered, nonhospitalized individuals sampled > 150 days after initial illness, suggesting greater sensitivity than serology at later time points and in individuals with less severe disease. T cell testing identified SARS-CoV-2 infection in 68% (55 of 81) of samples with undetectable nAb titers (<1:40) and in 37% (13 of 35) of samples classified as negative by 3 antibody assays.CONCLUSIONThese results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology.TRIAL REGISTRATIONSpecimens were accrued under trial NCT04338360 accessible at clinicaltrials.gov.FUNDINGThis work was funded by Adaptive Biotechnologies, Frederick National Laboratory for Cancer Research, NIAID, Fred Hutchinson Joel Meyers Endowment, Fast Grants, and American Society for Transplantation and Cell Therapy.


Subject(s)
COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , Humans , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2 , Severity of Illness Index , United States
6.
JCI Insight ; 7(10)2022 05 23.
Article in English | MEDLINE | ID: covidwho-1794307

ABSTRACT

T cells play a prominent role in orchestrating the immune response to viral diseases, but their role in the clinical presentation and subsequent immunity to SARS-CoV-2 infection remains poorly understood. As part of a population-based survey of the municipality of Vo', Italy, conducted after the initial SARS-CoV-2 outbreak, we sampled the T cell receptor (TCR) repertoires of the population 2 months after the initial PCR survey and followed up positive cases 9 and 15 months later. At 2 months, we found that 97.0% (98 of 101) of cases had elevated levels of TCRs associated with SARS-CoV-2. T cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the TCR repertoire were positively associated with neutralizing antibody titers, driven mostly by CD4+ T cells directed against spike protein. At the later time points, detection of these TCRs remained high, with 90.7% (78 of 96) and 86.2% (25 of 29) of individuals having detectable signal at 9 and 15 months, respectively. Forty-three individuals were vaccinated by month 15 and showed a significant increase in TCRs directed against spike protein. Taken together, these results demonstrate the central role of T cells in mounting an immune defense against SARS-CoV-2 that persists out to 15 months.


Subject(s)
COVID-19 , CD4-Positive T-Lymphocytes , Humans , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
7.
Inflamm Bowel Dis ; 28(7): 1130-1133, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-1784351

ABSTRACT

T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 vaccination in inflammatory bowel disease patients are poorly correlated. T-cell responses are preserved by most biologic therapies, but augmented by anti-tumor necrosis factor (anti-TNF) treatment. While anti-TNF therapy blunts the antibody response, cellular immunity after vaccination is robust.


Subject(s)
COVID-19 , Inflammatory Bowel Diseases , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Inflammatory Bowel Diseases/drug therapy , SARS-CoV-2 , T-Lymphocytes , Tumor Necrosis Factor Inhibitors/therapeutic use , Vaccination
8.
Open forum infectious diseases ; 8(Suppl 1):S77-S77, 2021.
Article in English | EuropePMC | ID: covidwho-1602523

ABSTRACT

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. Disclosures Thomas M. Snyder, PhD, Adaptive Biotechnologies (Employee, Shareholder) Rachel M. Gittelman, PhD, Adaptive Biotechnologies (Employee, Shareholder) Mark Klinger, PhD, Adaptive Biotechnologies (Employee, Shareholder) Damon H. May, PhD, Adaptive Biotechnologies (Employee, Shareholder) Edward J. Osborne, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ruth Taniguchi, PhD, Adaptive Biotechnologies (Employee, Shareholder) H. Jabran Zahid, PhD, Microsoft Research (Employee, Shareholder) Rebecca Elyanow, PhD, Adaptive Biotechnologies (Employee, Shareholder) Sudeb C. Dalai, MD, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ian M. Kaplan, PhD, Adaptive Biotechnologies (Employee, Shareholder) Jennifer N. Dines, MD, Adaptive Biotechnologies (Employee, Shareholder) Matthew T. Noakes, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ravi Pandya, PhD, Microsoft Research (Employee, Shareholder) Lance Baldo, MD, Adaptive Biotechnologies (Employee, Shareholder, Leadership Interest) James R. Heath, PhD, Merck (Research Grant or Support, Funding (from BARDA) for the ISB INCOV project, but had no role in planning the research or in writing the paper.) Joaquin Martinez-Lopez, MD, PhD, Adaptive Biotechnologies (Consultant) Jonathan M. Carlson, PhD, Microsoft Research (Employee, Shareholder) Harlan S. Robins, PhD, Adaptive Biotechnologies (Board Member, Employee, Shareholder)

9.
[Unspecified Source]; 2020.
Preprint in English | [Unspecified Source] | ID: ppcovidwho-292804

ABSTRACT

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.

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