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1.
Int J Biol Sci ; 18(15): 5591-5606, 2022.
Article in English | MEDLINE | ID: covidwho-2040345

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic respiratory infectious disease COVID-19. However, clinical manifestations and outcomes differ significantly among COVID-19 patients, ranging from asymptomatic to extremely severe, and it remains unclear what drives these disparities. Here, we studied 159 sequentially enrolled hospitalized patients with COVID-19-associated pneumonia from Brescia, Italy using the VirScan phage-display method to characterize circulating antibodies binding to 96,179 viral peptides encoded by 1,276 strains of human viruses. SARS-CoV-2 infection was associated with a marked increase in immune antibody repertoires against many known pathogenic and non-pathogenic human viruses. This antiviral antibody response was linked to longitudinal trajectories of disease severity and was further confirmed in additional 125 COVID-19 patients from the same geographical region in Northern Italy. By applying a machine-learning-based strategy, a viral exposure signature predictive of COVID-19-related disease severity linked to patient survival was developed and validated. These results provide a basis for understanding the role of memory B-cell repertoire to viral epitopes in COVID-19-related symptoms and suggest that a unique anti-viral antibody repertoire signature may be useful to define COVID-19 clinical severity.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Virome , Antiviral Agents , Epitopes
2.
Front Immunol ; 13: 841126, 2022.
Article in English | MEDLINE | ID: covidwho-1775675

ABSTRACT

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.


Subject(s)
Autoimmune Diseases , COVID-19 , Lupus Erythematosus, Systemic , Adaptor Proteins, Signal Transducing , Adenosine Triphosphatases , Adult , Autoantibodies , Autoantigens , Autoimmunity , COVID-19/complications , Child , Humans , Immunoglobulins, Intravenous , Ribonucleoproteins , Systemic Inflammatory Response Syndrome
4.
Front Immunol ; 12: 793197, 2021.
Article in English | MEDLINE | ID: covidwho-1674334

ABSTRACT

Background: Despite similar rates of infection, adults and children have markedly different morbidity and mortality related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Compared to adults, children have infrequent severe manifestations of acute infection but are uniquely at risk for the rare and often severe Multisystem Inflammatory Syndrome in Children (MIS-C) following infection. We hypothesized that these differences in presentation are related to differences in the magnitude and/or antigen specificity of SARS-CoV-2-specific T cell (CST) responses between adults and children. We therefore set out to measure the CST response in convalescent adults versus children with and without MIS-C following SARS-CoV-2 infection. Methods: CSTs were expanded from blood collected from convalescent children and adults post SARS-CoV-2 infection and evaluated by intracellular flow cytometry, surface markers, and cytokine production following stimulation with SARS-CoV-2-specific peptides. Presence of serum/plasma antibody to spike and nucleocapsid was measured using the luciferase immunoprecipitation systems (LIPS) assay. Findings: Twenty-six of 27 MIS-C patients, 7 of 8 non-MIS-C convalescent children, and 13 of 14 adults were seropositive for spike and nucleocapsid antibody. CST responses in MIS-C patients were significantly higher than children with uncomplicated SARS-CoV-2 infection, but weaker than CST responses in convalescent adults. Interpretation: Age-related differences in the magnitude of CST responses suggest differing post-infectious immunity to SARS-CoV-2 in children compared to adults post uncomplicated infection. Children with MIS-C have CST responses that are stronger than children with uncomplicated SARS-CoV-2 infection and weaker than convalescent adults, despite near uniform seropositivity.


Subject(s)
COVID-19/complications , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Antibodies, Viral/immunology , COVID-19/immunology , Child , Child, Preschool , Convalescence , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Infant , Male , Middle Aged , Phosphoproteins/immunology , Spike Glycoprotein, Coronavirus/immunology
5.
Pediatr Hematol Oncol ; 39(6): 571-579, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1671873

ABSTRACT

Recipients of anti-CD19 targeted therapies such as chimeric antigen receptor (CAR)-T cell are considered at high risk for complicated Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection due to prolonged B cell aplasia and immunosuppression. These patients represent a unique cohort and so far, immune responses to SARS-CoV-2 have not been well characterized in this setting. We report a pediatric patient with B-cell acute lymphoblastic leukemia (B-ALL) who had asymptomatic SARS-CoV-2 infection while receiving blinatumomab, followed by lymphodepletion (LD) and tisagenlecleucel, a CD19 targeting CAR-T therapy. The patient had a complete response to tisagenlecleucel, did not develop cytokine release syndrome, or worsening of SARS-CoV-2 during therapy. The patient had evidence of ongoing persistence of IgG antibody responses to spike and nucleocapsid after LD followed by tisagenlecleucel despite the B-cell aplasia. Further we were able to detect SARS-CoV-2 specific T-cells recognizing multiple viral structural proteins for several months following CAR-T. The T-cell response was polyfunctional and predominantly CD4 restricted. This data has important implications for the understanding of SARS-CoV-2 immunity in patients with impaired immune systems and the potential application of SARS-CoV-2-specific T-cell therapeutics to treat patients with blood cancers who receive B cell depleting therapy.


Subject(s)
COVID-19 , Receptors, Chimeric Antigen , Antigens, CD19 , COVID-19/therapy , Child , Humans , Immunity , Receptors, Antigen, T-Cell , SARS-CoV-2
6.
J Nephrol ; 35(3): 745-759, 2022 04.
Article in English | MEDLINE | ID: covidwho-1650680

ABSTRACT

BACKGROUND: Dialysis and kidney transplant patients with moderate-severe COVID-19 have a high mortality rate, around 30%, that is similar in the two populations, despite differences in their baseline characteristics. In these groups, the immunology of the disease has been poorly explored. METHODS: Thirty-two patients on dialysis or with kidney transplant and SARS-CoV-2 infection requiring hospitalization (COV group) were included in our study. Lymphocyte subsets, dendritic cell (DC) counts and monocyte activation were studied. SARS-CoV-2 anti-spike/anti-nucleocapsid were monitored, and baseline cytokines and chemokines were measured in 10 patients. RESULTS: The COV group, compared to healthy subjects and uninfected dialysis/kidney transplant controls, showed lower numbers of CD4 + and CD8 + T cells, Natural-Killer (NK), B cells, plasmacytoid and myeloid DCs, while the proportion of terminally differentiated B-cells was increased. IL6, IL10, IFN-α and chemokines involved in monocyte and neutrophil recruitment were higher in the COV group, compared to uninfected dialysis/kidney transplant controls. Patients with severe disease had lower CD4 + , CD8 + and B-cell counts and lower monocyte HLA-DR expression. Of note, when comparing dialysis and kidney transplant patients with COVID-19, the latter group presented lower NK and pDC counts and monocyte HLA-DR expression. Up to 60 days after symptom onset, kidney transplant recipients showed lower levels of anti-spike antibodies compared to dialysis patients. CONCLUSIONS: During SARS-CoV-2 infection, dialysis and kidney transplant patients manifest immunophenotype abnormalities; these are similar in the two groups, however kidney transplant recipients show more profound alterations of the innate immune system and lower anti-spike antibody response.


Subject(s)
COVID-19 , Kidney Transplantation , HLA-DR Antigens , Humans , Kidney Transplantation/adverse effects , Renal Dialysis/adverse effects , SARS-CoV-2 , Transplant Recipients
7.
J Clin Immunol ; 41(6): 1146-1153, 2021 08.
Article in English | MEDLINE | ID: covidwho-1384523

ABSTRACT

Immunocompromised patients, including those with inborn errors of immunity (IEI), may be at increased risk for severe or prolonged infections with SARS-CoV-2 (Zhu et al. N Engl J Med. 382:727-33, 2020; Guan et al. 2020; Minotti et al. J Infect. 81:e61-6, 2020). While antibody and T cell responses to SARS-CoV-2 structural proteins are well described in healthy convalescent donors, adaptive humoral and cellular immunity has not yet been characterized in patients with antibody deficiency (Grifoni et al. Cell. 181:1489-1501 e1415, 2020; Burbelo et al. 2020; Long et al. Nat Med. 26:845-8, 2020; Braun et al. 2020). Herein, we describe the clinical course, antibody, and T cell responses to SARS-CoV-2 structural proteins in a cohort of adult and pediatric patients with antibody deficiencies (n = 5) and controls (related and unrelated) infected with SARS-CoV-2. Five patients within the same family (3 with antibody deficiency, 2 immunocompetent controls) showed antibody responses to nucleocapsid and spike proteins, as well as SARS-CoV-2 specific T cell immunity at days 65-84 from onset of symptoms. No significant difference was identified between immunocompromised patients and controls. Two additional unrelated, adult patients with common variable immune deficiency were assessed. One did not show antibody response, but both demonstrated SARS-CoV-2-specific T cell immunity when evaluated 33 and 76 days, respectively, following SARS-CoV-2 diagnosis. This report is the first to show robust T cell activity and humoral immunity against SARS-CoV-2 structural proteins in some patients with antibody deficiency. Given the reliance on spike protein in most candidate vaccines (Folegatti et al. Lancet. 396:467-78, 2020; Jackson et al. N Engl J Med. 383:1920-31, 2020), the responses are encouraging. Additional studies will be needed to further define the timing of onset of immunity, longevity of the immune response, and variability of response in immunocompromised patients.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Common Variable Immunodeficiency/immunology , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adolescent , Adult , Carrier State , Cells, Cultured , Child , Female , Humans , Immunity, Humoral , Lymphocyte Activation , Male , Middle Aged , Mutation/genetics , Pedigree , Transmembrane Activator and CAML Interactor Protein/genetics , Whole Exome Sequencing , Young Adult
8.
Clin Infect Dis ; 73(11): e4223-e4228, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1387794

ABSTRACT

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become pandemic and the duration of protective immunity to the virus is unknown. Cases of persons reinfected with the virus are being reported with increasing frequency. At present it is unclear how common reinfection with SARS-CoV-2 is and how long serum antibodies and virus-specific T cells persist after infection. For many other respiratory virus infections, including influenza and the seasonal coronaviruses that cause colds, serum antibodies persist for only months to a few years and reinfections are very common. Here we review what is known about the duration of immunity and reinfection with coronaviruses, including SARS-CoV-2, as well as the duration of immunity to other viruses and virus vaccines. These findings have implications for the need of continued protective measures and for vaccines for persons previously infected with SARS-CoV-2.


Subject(s)
COVID-19 , Influenza Vaccines , Humans , Pandemics , Reinfection , SARS-CoV-2
9.
J Allergy Clin Immunol ; 148(5): 1192-1197, 2021 11.
Article in English | MEDLINE | ID: covidwho-1385788

ABSTRACT

BACKGROUND: SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients. OBJECTIVE: We sought to evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse events in a cohort of patients with IEIs. METHODS: Plasma was collected from 22 health care worker controls, 81 patients with IEIs, and 2 patients with thymoma; the plasma was collected before immunization, 1 to 6 days before the second dose of mRNA vaccine, and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson's Janssen vaccine. Anti-spike (anti-S) and anti-nucleocapsid antibody titers were measured by using a luciferase immunoprecipitation systems method. Information on T- and B-cell counts and use of immunosuppressive drugs was extracted from medical records, and information on vaccine-associated adverse events was collected after each dose. RESULTS: Anti-S antibodies were detected in 27 of 46 patients (58.7%) after 1 dose of mRNA vaccine and in 63 of 74 fully immunized patients (85.1%). A lower rate of seroconversion (7 of 11 [63.6%]) was observed in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Previous use of rituximab and baseline counts of less than 1000 CD3+ T cells/mL and less than 100 CD19+ B cells/mL were associated with lower anti-S IgG levels. No significant adverse events were reported. CONCLUSION: Vaccinating patients with IEIs is safe, but immunogenicity is affected by certain therapies and gene defects. These data may guide the counseling of patients with IEIs regarding prevention of SARS-CoV-2 infection and the need for subsequent boosts.


Subject(s)
Age Factors , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Polyendocrinopathies, Autoimmune/immunology , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adolescent , Adult , Aged , Antibodies, Viral/blood , Antibody Formation , COVID-19/drug therapy , COVID-19/genetics , Cohort Studies , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunization, Secondary , Immunogenicity, Vaccine , Immunoglobulin G/blood , Immunosuppressive Agents/therapeutic use , Lymphocyte Count , Male , Middle Aged , Phosphoproteins/immunology , Polyendocrinopathies, Autoimmune/drug therapy , Polyendocrinopathies, Autoimmune/genetics , Rituximab/therapeutic use , Seroconversion , Spike Glycoprotein, Coronavirus/immunology , Young Adult
10.
Sci Adv ; 7(31)2021 Jul.
Article in English | MEDLINE | ID: covidwho-1334521

ABSTRACT

Interpretation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurveillance studies is limited by poorly defined performance of antibody assays over time in individuals with different clinical presentations. We measured antibody responses in plasma samples from 128 individuals over 160 days using 14 assays. We found a consistent and strong effect of disease severity on antibody magnitude, driven by fever, cough, hospitalization, and oxygen requirement. Responses to spike protein versus nucleocapsid had consistently higher correlation with neutralization. Assays varied substantially in sensitivity during early convalescence and time to seroreversion. Variability was dramatic for individuals with mild infection, who had consistently lower antibody titers, with sensitivities at 6 months ranging from 33 to 98% for commercial assays. Thus, the ability to detect previous infection by SARS-CoV-2 is highly dependent on infection severity, timing, and the assay used. These findings have important implications for the design and interpretation of SARS-CoV-2 serosurveillance studies.

11.
Cell ; 184(7): 1836-1857.e22, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1077815

ABSTRACT

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.


Subject(s)
COVID-19/immunology , Cytokines/metabolism , Dendritic Cells/metabolism , Gene Expression/immunology , Killer Cells, Natural/metabolism , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , COVID-19/mortality , Case-Control Studies , Dendritic Cells/cytology , Female , Humans , Killer Cells, Natural/cytology , Longitudinal Studies , Male , Middle Aged , Transcriptome/immunology , Young Adult
12.
J Pediatric Infect Dis Soc ; 9(6): 769-771, 2020 Dec 31.
Article in English | MEDLINE | ID: covidwho-1072398

ABSTRACT

Evidence for in utero transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is growing but not definitive. We present a case of neonatal infection that supports in utero transmission of SARS-CoV-2 and provides insight into the hematogenous spread from mother to fetus.


Subject(s)
COVID-19/transmission , Infant, Newborn, Diseases/virology , Infectious Disease Transmission, Vertical , Pregnancy Complications, Infectious/virology , COVID-19/complications , COVID-19 Testing , Female , Fetal Blood/virology , Humans , Infant, Newborn , Infant, Newborn, Diseases/diagnosis , Infant, Newborn, Diseases/etiology , Male , Placenta/virology , Pregnancy , RNA, Viral/blood , RNA, Viral/urine , SARS-CoV-2/genetics
14.
JCI Insight ; 6(1)2021 01 11.
Article in English | MEDLINE | ID: covidwho-1027164

ABSTRACT

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Biomarkers , COVID-19/genetics , COVID-19/therapy , Calgranulin B/genetics , Calgranulin B/immunology , Case-Control Studies , Chemokine CCL2/genetics , Chemokine CCL2/immunology , Chemokine CXCL9/genetics , Chemokine CXCL9/immunology , Enzyme Inhibitors/therapeutic use , Female , Ferritins/genetics , Ferritins/immunology , Gene Expression Profiling , Humans , Hydroxychloroquine/therapeutic use , Immunologic Factors/therapeutic use , Interferon Type I/genetics , Interferon Type I/immunology , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-1 Receptor-Like 1 Protein/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-15/genetics , Interleukin-15/immunology , Interleukin-2/genetics , Interleukin-2/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Lactoferrin/genetics , Lactoferrin/immunology , Lipocalin-2/genetics , Lipocalin-2/immunology , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/immunology , Middle Aged , Multivariate Analysis , NF-kappa B/genetics , NF-kappa B/immunology
15.
Blood ; 137(2): 185-189, 2021 01 14.
Article in English | MEDLINE | ID: covidwho-953565

ABSTRACT

Vaccinations are effective in preventing infections; however, it is unknown if patients with chronic lymphocytic leukemia (CLL) who are treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitors (BTKi's) respond to novel adjuvanted vaccines. Understanding the effect of BTKi's on humoral immunity is timely because BTKi's are widely used and vaccination against coronavirus disease 2019 is urgently needed. In 2 open-label, single-arm clinical trials, we measured the effect of BTKi's on de novo immune response against recombinant hepatitis B vaccine (HepB-CpG) and recall response against recombinant zoster vaccine (RZV) in CLL patients who were TN or on BTKi. The primary end point was serologic response to HepB-CpG (anti-hepatitis B surface antibodies ≥10 mIU/mL) and RZV (≥fourfold increase in anti-glycoprotein E). The response rate to HepB-CpG was lower in patients on BTKi (3.8%; 95% confidence interval [CI], 0.7-18.9) than patients who were TN (28.1%; 95% CI, 15.6-45.4; P = .017). In contrast, the response rate to RZV did not differ significantly between the BTKi (41.5%; 95% CI, 27.8-56.6) and TN cohorts (59.1%; 95% CI, 38.7-76.7; P = .2). BTKi's were associated with a decreased de novo immune response following HepB-CpG, whereas recall immune response following RZV was not significantly affected by BTKi therapy. These trials were registered at www.clinicaltrials.gov as #NCT03685708 (Hep-CpG) and #NCT03702231 (RZV).


Subject(s)
Hepatitis B Vaccines/immunology , Herpes Zoster Vaccine/immunology , Immunity , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Protein Kinase Inhibitors/adverse effects , Vaccines, Synthetic/immunology , Adjuvants, Immunologic , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Aged , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Middle Aged , Patient Outcome Assessment , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Vaccination
16.
Blood ; 136(25): 2905-2917, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-890058

ABSTRACT

T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been described in recovered patients, and may be important for immunity following infection and vaccination as well as for the development of an adoptive immunotherapy for the treatment of immunocompromised individuals. In this report, we demonstrate that SARS-CoV-2-specific T cells can be expanded from convalescent donors and recognize immunodominant viral epitopes in conserved regions of membrane, spike, and nucleocapsid. Following in vitro expansion using a good manufacturing practice-compliant methodology (designed to allow the rapid translation of this novel SARS-CoV-2 T-cell therapy to the clinic), membrane, spike, and nucleocapsid peptides elicited interferon-γ production, in 27 (59%), 12 (26%), and 10 (22%) convalescent donors (respectively), as well as in 2 of 15 unexposed controls. We identified multiple polyfunctional CD4-restricted T-cell epitopes within a highly conserved region of membrane protein, which induced polyfunctional T-cell responses, which may be critical for the development of effective vaccine and T-cell therapies. Hence, our study shows that SARS-CoV-2 directed T-cell immunotherapy targeting structural proteins, most importantly membrane protein, should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders or after bone marrow transplantation to achieve antiviral control while mitigating uncontrolled inflammation.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Cell Culture Techniques/methods , Immunotherapy, Adoptive/methods , SARS-CoV-2/immunology , Adult , Aged , COVID-19/drug therapy , Epitopes, T-Lymphocyte/immunology , Female , Humans , Immunodominant Epitopes/immunology , Male , Membrane Proteins/immunology , Middle Aged , Viral Proteins/immunology , Young Adult
17.
J Infect Dis ; 222(2): 206-213, 2020 06 29.
Article in English | MEDLINE | ID: covidwho-618807

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is associated with respiratory-related disease and death. Assays to detect virus-specific antibodies are important to understand the prevalence of infection and the course of the immune response. METHODS: Quantitative measurements of plasma or serum antibodies to the nucleocapsid and spike proteins were analyzed using luciferase immunoprecipitation system assays in 100 cross-sectional or longitudinal samples from patients with SARS-CoV-2 infection. A subset of samples was tested both with and without heat inactivation. RESULTS: At >14 days after symptom onset, antibodies against SARS-CoV-2 nucleocapsid protein showed 100% sensitivity and 100% specificity, whereas antibodies to spike protein were detected with 91% sensitivity and 100% specificity. Neither antibody levels nor the rate of seropositivity were significantly reduced by heat inactivation of samples. Analysis of daily samples from 6 patients with COVID-19 showed anti-nucleocapsid and spike protein antibodies appearing between days 8 and 14 after initial symptoms. Immunocompromised patients generally had a delayed antibody response to SARS-CoV-2, compared with immunocompetent patients. CONCLUSIONS: Antibody to the nucleocapsid protein of SARS-CoV-2 is more sensitive than spike protein antibody for detecting early infection. Analyzing heat-inactivated samples with a luciferase immunoprecipitation system assay is a safe and sensitive method for detecting SARS-CoV-2 antibodies.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Clinical Laboratory Techniques , Coronavirus Infections/immunology , Immunoprecipitation , Nucleocapsid Proteins/immunology , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , COVID-19 , COVID-19 Testing , Coronavirus Infections/diagnosis , Coronavirus Nucleocapsid Proteins , Female , Hot Temperature , Humans , Immunocompetence , Immunocompromised Host , Luciferases , Male , Middle Aged , Pandemics , Phosphoproteins , Retrospective Studies , SARS-CoV-2 , Sensitivity and Specificity , Time Factors
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