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1.
Nat Med ; 28(5): 1050-1062, 2022 05.
Article in English | MEDLINE | ID: covidwho-1701612

ABSTRACT

Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.


Subject(s)
COVID-19 , COVID-19/complications , COVID-19/genetics , Child , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/genetics , T-Lymphocytes
2.
Open Forum Infect Dis ; 9(1): ofab575, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1631248

ABSTRACT

BACKGROUND: The relationship between postvaccination symptoms and strength of antibody responses is unclear. The goal of this study was to determine whether adverse effects caused by vaccination with the Pfizer/BioNTech BNT162b2 vaccine are associated with the magnitude of vaccine-induced antibody levels. METHODS: We conducted a single-center, observational cohort study consisting of generally healthy adult participants that were not severely immunocompromised, had no history of coronavirus disease 2019, and were seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein before vaccination. Severity of vaccine-associated symptoms was obtained through participant-completed questionnaires. Testing for immunoglobulin G antibodies against SARS-CoV-2 spike protein and receptor-binding domain was conducted using microsphere-based multiplex immunoassays performed on serum samples collected at monthly visits. Neutralizing antibody titers were determined by microneutralization assays. RESULTS: Two hundred six participants were evaluated (69.4% female, median age 41.5 years old). We found no correlation between vaccine-associated symptom severity scores and vaccine-induced antibody titers 1 month after vaccination. We also observed that (1) postvaccination symptoms were inversely correlated with age and weight and more common in women, (2) systemic symptoms were more frequent after the second vaccination, (3) high symptom scores after first vaccination were predictive of high symptom scores after second vaccination, and (4) older age was associated with lower titers. CONCLUSIONS: Lack of postvaccination symptoms after receipt of the BNT162b2 vaccine does not equate to lack of vaccine-induced antibodies 1 month after vaccination.

3.
Open forum infectious diseases ; 8(Suppl 1):S325-S326, 2021.
Article in English | EuropePMC | ID: covidwho-1602651

ABSTRACT

Background Approximately 10-20% of patients with critical COVID-19 harbor neutralizing autoantibodies (auto-Abs) that target type I interferons (IFN), a family of cytokines that induce critical innate immune defense mechanisms upon viral infection. Studies to date indicate that these auto-Abs are mostly detected in men over age 65. Methods We screened for type I IFN serum auto-Abs in sera collected < 21 days post-symptom onset in a subset of 103 COVID-19 inpatients and 24 outpatients drawn from a large prospective cohort study of SARS-CoV-2 infected patients enrolled across U.S. Military Treatment Facilities. The mean age of this n = 127 subset of study participants was 55.2 years (SD = 15.2 years, range 7.7 – 86.2 years), and 86/127 (67.7%) were male. Results Among those hospitalized 49/103 (47.6%) had severe COVID-19 (required at least high flow oxygen), and nine subjects died. We detected neutralizing auto-Abs against IFN-α, IFN-ω, or both, in four inpatients (3.9%, 8.2% of severe cases), with no auto-Abs detected in outpatients. Three of these patients were white males over the age of 62, all with multiple comorbidities;two of whom died and the third requiring high flow oxygen therapy. The fourth patient was a 36-year-old Hispanic female with a history of obesity who required mechanical ventilation during her admission for COVID-19. Conclusion These findings support the association between type I IFN auto-antibody production and life-threatening COVID-19. With further validation, reliable high-throughput screening for type I IFN auto-Abs may inform diagnosis, pathogenesis and treatment strategies for COVID-19, particularly in older males. Our finding of type I IFN auto-Ab production in a younger female prompts further study of this autoimmune phenotype in a broader population. Disclosures David A. Lindholm, MD, American Board of Internal Medicine (Individual(s) Involved: Self): Member of Auxiliary R&D Infectious Disease Item-Writer Task Force. No financial support received. No exam questions will be disclosed ., Other Financial or Material Support David Tribble, M.D., DrPH, Astra Zeneca (Other Financial or Material Support, HJF, in support of USU IDCRP, funded under a CRADA to augment the conduct of an unrelated Phase III COVID-19 vaccine trial sponsored by AstraZeneca as part of USG response (unrelated work)) Simon Pollett, MBBS, Astra Zeneca (Other Financial or Material Support, HJF, in support of USU IDCRP, funded under a CRADA to augment the conduct of an unrelated Phase III COVID-19 vaccine trial sponsored by AstraZeneca as part of USG response (unrelated work))

4.
Open forum infectious diseases ; 8(Suppl 1):S333-S333, 2021.
Article in English | EuropePMC | ID: covidwho-1602214

ABSTRACT

Background The initial response of immune cells against respiratory viruses often determines the severity and duration of disease. The early trajectory of the immune response during infection with SARS-CoV-2 remains poorly understood. Dysregulation of innate immune factors that facilitate viral clearance and the adaptive response, such as type I interferons, have been implicated in severe COVID-19. However, collection of biological samples during the first seven days post-symptom onset has posed a logistical challenge, limiting our knowledge surrounding the immune responses that drive protection versus immunopathology. Methods From March 2020, Military Health System beneficiaries presenting with a positive SARS-CoV-2 test, a COVID-19 like illness, or a high-risk SARS-CoV-2 exposure at nine military medical treatment facilities across the United States were eligible for enrollment in our longitudinal cohort study, which included collection of respiratory sample, sera, plasma, and peripheral blood mononuclear cells (PBMCs). Twenty-five SARS-CoV-2 infected study participants provided samples with in the first seven days of symptom onset, fifteen of whom were hospitalized with COVID-19. We employed multiparameter spectral flow cytometry to comprehensively analyze the early trajectory of the innate and adaptive immune responses. Results We discovered that early activation of critical antigen presenting cell subsets was impaired upon comparing inpatients with outpatients, correlating with decreased antigen-experienced T cell responses. Specifically, we noted reduced expression of key costimulatory molecules, CD80 and CD86, on conventional dendritic cells that are required for viral antigen-specific T cell priming. Reduction in CD38, a marker of activation was also observed on inpatient dendritic cell subsets. Conclusion Reduced antigen presenting cell activation and expression of ligands that facilitate T cell engagement may impede the efficient clearance of SARS-CoV-2, coinciding with more severe disease in our cohort. Further analysis of the functional activation of early innate immune responses triggered by SARS-CoV-2 may unveil new immune biomarkers and therapeutic targets to predict and prevent severe disease associated with inadequate T cell immunity. Disclosures Simon Pollett, MBBS, Astra Zeneca (Other Financial or Material Support, HJF, in support of USU IDCRP, funded under a CRADA to augment the conduct of an unrelated Phase III COVID-19 vaccine trial sponsored by AstraZeneca as part of USG response (unrelated work))

5.
J Infect Dis ; 224(12): 2010-2019, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1574912

ABSTRACT

BACKGROUND: Characterizing the longevity and quality of cellular immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enhances understanding of coronavirus disease 2019 (COVID-19) immunity that influences clinical outcomes. Prior studies suggest SARS-CoV-2-specific T cells are present in peripheral blood 10 months after infection. Analysis of the function, durability, and diversity of cellular response long after natural infection, over a range of ages and disease phenotypes, is needed to identify preventative and therapeutic interventions. METHODS: We identified participants in our multisite longitudinal, prospective cohort study 12 months after SARS-CoV-2 infection representing a range of disease severity. We investigated function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry, and compared magnitude of SARS-CoV-2-specific antibodies. RESULTS: SARS-CoV-2-specific antibodies and T cells were detected 12 months postinfection. Severe acute illness was associated with higher frequencies of SARS-CoV-2-specific CD4 T cells and antibodies at 12 months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity. CONCLUSIONS: SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12 months postinfection, with higher frequency noted in those who experienced severe disease.


Subject(s)
COVID-19/immunology , COVID-19/virology , Immunologic Memory , SARS-CoV-2/immunology , T-Lymphocyte Subsets/immunology , Adult , Antibodies, Viral , Antigens, Viral , Biomarkers , COVID-19/diagnosis , COVID-19/epidemiology , Female , Humans , Immunity, Cellular , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Severity of Illness Index , T-Lymphocyte Subsets/metabolism , Time Factors
6.
J Infect Dis ; 224(12): 2010-2019, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1483460

ABSTRACT

BACKGROUND: Characterizing the longevity and quality of cellular immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enhances understanding of coronavirus disease 2019 (COVID-19) immunity that influences clinical outcomes. Prior studies suggest SARS-CoV-2-specific T cells are present in peripheral blood 10 months after infection. Analysis of the function, durability, and diversity of cellular response long after natural infection, over a range of ages and disease phenotypes, is needed to identify preventative and therapeutic interventions. METHODS: We identified participants in our multisite longitudinal, prospective cohort study 12 months after SARS-CoV-2 infection representing a range of disease severity. We investigated function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry, and compared magnitude of SARS-CoV-2-specific antibodies. RESULTS: SARS-CoV-2-specific antibodies and T cells were detected 12 months postinfection. Severe acute illness was associated with higher frequencies of SARS-CoV-2-specific CD4 T cells and antibodies at 12 months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity. CONCLUSIONS: SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12 months postinfection, with higher frequency noted in those who experienced severe disease.


Subject(s)
COVID-19/immunology , COVID-19/virology , Immunologic Memory , SARS-CoV-2/immunology , T-Lymphocyte Subsets/immunology , Adult , Antibodies, Viral , Antigens, Viral , Biomarkers , COVID-19/diagnosis , COVID-19/epidemiology , Female , Humans , Immunity, Cellular , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Severity of Illness Index , T-Lymphocyte Subsets/metabolism , Time Factors
7.
BMC Infect Dis ; 21(1): 544, 2021 Jun 09.
Article in English | MEDLINE | ID: covidwho-1262498

ABSTRACT

BACKGROUND: SARS-CoV-2 is a recently emerged pandemic coronavirus (CoV) capable of causing severe respiratory illness. However, a significant number of infected people present as asymptomatic or pauci-symptomatic. In this prospective assessment of at-risk healthcare workers (HCWs) we seek to determine whether pre-existing antibody or T cell responses to previous seasonal human coronavirus (HCoV) infections affect immunological or clinical responses to SARS-CoV-2 infection or vaccination. METHODS: A cohort of 300 healthcare workers, confirmed negative for SARS-CoV-2 exposure upon study entry, will be followed for up to 1 year with monthly serology analysis of IgM and IgG antibodies against the spike proteins of SARS-CoV-2 and the four major seasonal human coronavirus - HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63. Participants will complete monthly questionnaires that ask about Coronavirus Disease 2019 (COVID-19) exposure risks, and a standardized, validated symptom questionnaire (scoring viral respiratory disease symptoms, intensity and severity) at least twice monthly and any day when any symptoms manifest. SARS-CoV-2 PCR testing will be performed any time participants develop symptoms consistent with COVID-19. For those individuals that seroconvert and/or test positive by SARS-CoV-2 PCR, or receive the SARS-CoV-2 vaccine, additional studies of T cell activation and cytokine production in response to SARS-CoV-2 peptide pools and analysis of Natural Killer cell numbers and function will be conducted on that participant's cryopreserved baseline peripheral blood mononuclear cells (PBMCs). Following the first year of this study we will further analyze those participants having tested positive for COVID-19, and/or having received an authorized/licensed SARS-CoV-2 vaccine, quarterly (year 2) and semi-annually (years 3 and 4) to investigate immune response longevity. DISCUSSION: This study will determine the frequency of asymptomatic and pauci-symptomatic SARS-CoV-2 infection in a cohort of at-risk healthcare workers. Baseline and longitudinal assays will determine the frequency and magnitude of anti-spike glycoprotein antibodies to the seasonal HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63, and may inform whether pre-existing antibodies to these human coronaviruses are associated with altered COVID-19 disease course. Finally, this study will evaluate whether pre-existing immune responses to seasonal HCoVs affect the magnitude and duration of antibody and T cell responses to SARS-CoV-2 vaccination, adjusting for demographic covariates.


Subject(s)
COVID-19/immunology , Health Personnel/statistics & numerical data , SARS-CoV-2/immunology , Seroconversion , Vaccination/statistics & numerical data , Antibodies, Viral/blood , Antibodies, Viral/immunology , Asymptomatic Infections , COVID-19 Vaccines/immunology , Coronavirus/immunology , Cross Reactions , Humans , Prospective Studies , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology
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