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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-337276

ABSTRACT

The SARS-CoV-2 Omicron variant is characterized by substantial changes in the antigenic structure of the Spike (S) protein. Therefore, we analyzed whether these changes impact the sensitivity of commercial anti-SARS-CoV-2 antibody assays. Sera from 37 convalescent individuals after primary Omicron infection were tested with 20 commercial anti-SARS-CoV-2 immunoassays. As controls, we used samples from 43 individuals after primary infection with an ancestral wildtype strain. Notably, in Omicron convalescents, there was a statistically significant reduction in the sensitivity of all antibody assays containing S or its receptor-binding-domain (RBD) as antigens. Furthermore, antibody levels quantified by these assays displayed a weaker correlation with Omicron-specific neutralizing antibody titers than with those against the wildtype. In contrast, the sensitivity of nucleocapsid-protein-specific immunoassays was similar in wildtype and Omicron-infected subjects. In summary, the antigenic changes in the Omicron S lead to reduced detection rates in commercial S- and RBD-specific antibody assays, impairing their diagnostic performance.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-333086

ABSTRACT

The recently emerged Omicron variant is the most antigenically distinct SARS-CoV-2 variant of concern to date. As the heavily mutated spike protein enables escape from neutralizing antibodies, we studied the neutralizing activities of sera after Omicron BA.1 and BA.2 infections of naïve and vaccinated individuals. We show that primary BA.1 infections yielded reduced neutralizing antibody titers against wildtype (WT), Delta, and BA.2, while serum samples from individuals after BA.2 infection showed no cross-neutralization against the other variants. Fully vaccinated individuals were still able to neutralize both Omicron sub-lineages up to three months after vaccination, and Omicron-breakthrough infections showed equal cross-neutralizing activities against WT, Delta, BA.1, and BA.2. Our data demonstrate that Omicron variants are able to enhance cross-neutralizing antibodies in pre-immune individuals. Primary infections with one of the Omicron sub-lineages, however, induced variant-specific neutralizing antibodies. In particular, BA.2 infections generated a sub-lineage-specific response, emphasizing its antigenic distance.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314444

ABSTRACT

Background: Patients with neuroimmunological disorders on anti-CD20 therapy are at increased risk of severe COVID-19. However, little is known about SARS-CoV-2 vaccine efficacy in this cohort. In particular, the impact of B cell depletion on humoral and cellular immune responses to SARS-CoV-2 vaccination remains poorly defined. No study has addressed vaccine responses to the SARS-CoV-2 delta variant in immunocompromised individuals so far.Methods: In this prospective cohort study we investigated humoral and cellular responses in serial samples from 164 individuals after SARS-CoV-2 mRNA vaccination (82 patients with neuroimmunological disorders on anti-CD20 therapy and 82 healthy controls). Antibodies were quantified using the Elecsys anti-SARS-CoV-2 S immunoassay against the receptor-binding (RBD) domain. T cell responses against the SARS-CoV-2 Wuhan strain and the delta variant were assessed by IFN-g enzyme-linked immunosorbent spot assays. Findings: Following vaccination, SARS-CoV-2 –specific antibodies were detected in 57/82 (70%) patients compared to 82/82 (100%) healthy controls (p<0·001). Seroconversion rates and antibody levels were lower in B cell-depleted (<1 B cell/mcl) patients compared to non-depleted (≥ 1 B cell/mcl) patients (p<0·001). B cell levels ≥ 1 cell/mcl were sufficient to induce anti-SARS-CoV-2-S antibody responses. In contrast to the antibody response, most B cell-depleted patients generated a T-cell response against the SARS-CoV-2 Wuhan strain and the delta variant that was more robust in frequency (p<0·05) and magnitude (p<0·01) compared to non-depleted patients and persisted for at least six weeks.Interpretation: Humoral immunity following SARS-CoV-2 mRNA vaccination can be achieved in patients on anti-CD20 therapy once B cells start to repopulate. In the absence of B cells, a robust and stable T cell response is generated which may provide a potent defense against severe COVID-19 in this high-risk patient population. Funding Information: Funded partly by a Medical-Scientific fund of the Major of the federal capital of Vienna (grant Covid003).Declaration of Interests: BK has received honoraria for speaking and for consulting from Biogen, BMS-Celgene, Johnson&Johnson, Merck, Novartis, Roche, Teva and Sanofi-Genzyme outside of the submitted work. No conflict of interest with respect to the present study. FL has received honoraria for speaking and consulting from Almirall, Biogen-Idec, Celgene BMS, MedDay, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Genzyme, Santhera;Schering, Teva-Ratiopharm. There are no conflicts of interest with respect to the present study, PR has received honoraria for speaking and for consulting from Alexion, Almirall, Amicus, Biogen, Merck, Novartis, Roche, Teva, Sandoz, and Sanofi Genzyme outside of the submitted work. He has received research grants from Amicus, Biogen, Merck and Roche outside the submitted work. GZ recieved speaking honoria from biogen and has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. No conflict of interest regarding this study, GB has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Novartis, Roche, Sanofi-Genzyme and Teva. He has received financial support in the past 12 months by unrestricted research grants (Celgene/BMS, Novartis). No conflict of interest with respect to the present study, ADB declares no conflict of interest related to the content of this article. Independent of this study, ADB has participated in meetings sponsored by or received speaker honoraria or travel funding from Biogen, Merck, Novartis, Roche, Celgene (BMS), and Sanofi. She has received an unrestricted grant from Merck GmbH, an affiliate of Merck KGaA and is currently supported by a research grant from Biogen. TB has no particular conflicts of interest regar ing the present study. In general, he has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Bayer, Biogen, Biologix, Bionorica, Genzyme, GSK, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, TG Pharmaceuticals, TEVA ratiopharm and UCB. His institution has received financial support in the last 12 months by unrestricted research grants (Biogen, Bayer, Merck, Novartis, Sanofi/Genzyme, and TEVA ratiopharm) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, and TEVA. LS, HH, RT, FZ, WR, KZ, IW, AS, MG, MM, KR, SW, JHA, ST report no conflicts of interest.Ethics Approval Statement: Subjects gave written informed consent. The study was approved by the ethics committee of the Medical University of Vienna, Austria, EK Nr. 1073/2021.

4.
Ann Neurol ; 91(3): 342-352, 2022 03.
Article in English | MEDLINE | ID: covidwho-1648414

ABSTRACT

OBJECTIVE: The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination in patients with various neuroimmunologic disorders on anti-CD20 therapy. This included an analysis of the T cell vaccine response to the SARS-CoV-2 Delta variant. METHODS: We investigated prospectively humoral and cellular responses to SARS-CoV-2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti-CD20 therapy and 82 age- and sex-matched healthy controls. For quantification of antibodies, the Elecsys anti-SARS-CoV-2 viral spike (S) immunoassay against the receptor-binding domain (RBD) was used. IFN-gamma enzyme-linked immunosorbent spot assays were performed to assess T cell responses against the SARS-CoV-2 Wuhan strain and the Delta variant. RESULTS: SARS-CoV-2-specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p < 0.001). In patients without detectable B cells (<1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p < 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti-CD20 treated patients. In contrast to the antibody response, the T-cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p < 0.05) and magnitude (p < 0.01) in B-cell depleted compared to nondepleted patients. INTERPRETATION: Antibody responses to SARS-CoV-2 mRNA vaccinnation can be attained in patients on anti-CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID-19) in this high-risk population. ANN NEUROL 2022;91:342-352.


Subject(s)
Autoimmune Diseases of the Nervous System/immunology , B-Lymphocytes/immunology , COVID-19 Vaccines/administration & dosage , Immunity, Cellular/immunology , Immunity, Humoral/immunology , SARS-CoV-2/immunology , Adult , Autoimmune Diseases of the Nervous System/blood , Autoimmune Diseases of the Nervous System/epidemiology , B-Lymphocytes/metabolism , COVID-19/epidemiology , COVID-19/prevention & control , Cohort Studies , Female , Humans , Male , Middle Aged , Neuroimmunomodulation/immunology , Prospective Studies , SARS-CoV-2/metabolism
5.
Ann Rheum Dis ; 80(10): 1345-1350, 2021 10.
Article in English | MEDLINE | ID: covidwho-1394067

ABSTRACT

OBJECTIVES: Evidence suggests that B cell-depleting therapy with rituximab (RTX) affects humoral immune response after vaccination. It remains unclear whether RTX-treated patients can develop a humoral and T-cell-mediated immune response against SARS-CoV-2 after immunisation. METHODS: Patients under RTX treatment (n=74) were vaccinated twice with either mRNA-1273 or BNT162b2. Antibodies were quantified using the Elecsys Anti-SARS-CoV-2 S immunoassay against the receptor-binding domain (RBD) of the spike protein and neutralisation tests. SARS-CoV-2-specific T-cell responses were quantified by IFN-γ enzyme-linked immunosorbent spot assays. Prepandemic healthy individuals (n=5), as well as healthy individuals (n=10) vaccinated with BNT162b2, served as controls. RESULTS: All healthy controls developed antibodies against the SARS-CoV-2 RBD of the spike protein, but only 39% of the patients under RTX treatment seroconverted. Antibodies against SARS-CoV-2 RBD significantly correlated with neutralising antibodies (τ=0.74, p<0.001). Patients without detectable CD19+ peripheral B cells (n=36) did not develop specific antibodies, except for one patient. Circulating B cells correlated with the levels of antibodies (τ=0.4, p<0.001). However, even patients with a low number of B cells (<1%) mounted detectable SARS-CoV-2-specific antibody responses. SARS-CoV-2-specific T cells were detected in 58% of the patients, independent of a humoral immune response. CONCLUSIONS: The data suggest that vaccination can induce SARS-CoV-2-specific antibodies in RTX-treated patients, once peripheral B cells at least partially repopulate. Moreover, SARS-CoV-2-specific T cells that evolved in more than half of the vaccinated patients may exert protective effects independent of humoral immune responses.


Subject(s)
Antirheumatic Agents/therapeutic use , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunocompromised Host/immunology , Immunogenicity, Vaccine/immunology , Rituximab/therapeutic use , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , B-Lymphocytes/immunology , Female , Humans , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Immunogenicity, Vaccine/drug effects , Male , Middle Aged , SARS-CoV-2 , T-Lymphocytes/immunology
6.
Ann Rheum Dis ; 80(10): 1345-1350, 2021 10.
Article in English | MEDLINE | ID: covidwho-1319387

ABSTRACT

OBJECTIVES: Evidence suggests that B cell-depleting therapy with rituximab (RTX) affects humoral immune response after vaccination. It remains unclear whether RTX-treated patients can develop a humoral and T-cell-mediated immune response against SARS-CoV-2 after immunisation. METHODS: Patients under RTX treatment (n=74) were vaccinated twice with either mRNA-1273 or BNT162b2. Antibodies were quantified using the Elecsys Anti-SARS-CoV-2 S immunoassay against the receptor-binding domain (RBD) of the spike protein and neutralisation tests. SARS-CoV-2-specific T-cell responses were quantified by IFN-γ enzyme-linked immunosorbent spot assays. Prepandemic healthy individuals (n=5), as well as healthy individuals (n=10) vaccinated with BNT162b2, served as controls. RESULTS: All healthy controls developed antibodies against the SARS-CoV-2 RBD of the spike protein, but only 39% of the patients under RTX treatment seroconverted. Antibodies against SARS-CoV-2 RBD significantly correlated with neutralising antibodies (τ=0.74, p<0.001). Patients without detectable CD19+ peripheral B cells (n=36) did not develop specific antibodies, except for one patient. Circulating B cells correlated with the levels of antibodies (τ=0.4, p<0.001). However, even patients with a low number of B cells (<1%) mounted detectable SARS-CoV-2-specific antibody responses. SARS-CoV-2-specific T cells were detected in 58% of the patients, independent of a humoral immune response. CONCLUSIONS: The data suggest that vaccination can induce SARS-CoV-2-specific antibodies in RTX-treated patients, once peripheral B cells at least partially repopulate. Moreover, SARS-CoV-2-specific T cells that evolved in more than half of the vaccinated patients may exert protective effects independent of humoral immune responses.


Subject(s)
Antirheumatic Agents/therapeutic use , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunocompromised Host/immunology , Immunogenicity, Vaccine/immunology , Rituximab/therapeutic use , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , B-Lymphocytes/immunology , Female , Humans , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Immunogenicity, Vaccine/drug effects , Male , Middle Aged , SARS-CoV-2 , T-Lymphocytes/immunology
7.
J Clin Microbiol ; 59(5)2021 04 20.
Article in English | MEDLINE | ID: covidwho-1195818

ABSTRACT

In this study, we comprehensively analyzed multispecific antibody kinetics of different immunoglobulins in hospitalized patients with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Three hundred fifty-four blood samples longitudinally obtained from 81 IgG-seroconverting progressed coronavirus disease 2019 (CoVID-19) patients were quantified for spike 1 (S1), S2, and nucleocapsid protein (NCP)-specific IgM, IgA, IgG, and total Ig antibodies using a microarray, 11 different enzyme-linked immunosorbent assays (ELISAs)/chemiluminescence immunoassays (CLIAs), and 1 rapid test by seven manufacturers. The assays' specificity was assessed in 130 non-CoVID-19 pneumonia patients. Using the microarray, NCP-specific IgA and IgG antibodies continuously displayed higher detection rates during acute CoVID-19 than S1- and S2-specific ones. S1-specific IgG antibodies, however, reached higher peak values. Until the 26th day post-symptom onset, all patients developed IgG responses against S1, S2, and NCP. Although detection rates by ELISAs/CLIAs generally resembled those of the microarray, corresponding to the target antigen, sensitivities and specificities varied among all tests. Notably, patients with more severe CoVID-19 displayed higher IgG and IgA levels, but this difference was mainly observed with S1-specific immunoassays. In patients with high SARS-CoV-2 levels in the lower respiratory tract, we observed high detection rates of IgG and total Ig immunoassays with a particular rise of S1-specific IgG antibodies when viral concentrations in the tracheal aspirate subsequently declined over time. In summary, our study demonstrates that differences in sensitivity among commercial immunoassays during acute SARS-CoV-2 infection are only partly related to the target antigen. Importantly, our data indicate that NCP-specific IgA and IgG antibodies are detected earlier, while higher S1-specific IgA antibody levels occur in severely ill patients.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Immunoassay/methods , Coronavirus Nucleocapsid Proteins/immunology , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Kinetics , Phosphoproteins/immunology , SARS-CoV-2 , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/immunology
8.
Sci Immunol ; 6(57)2021 03 04.
Article in English | MEDLINE | ID: covidwho-1148101

ABSTRACT

CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19 , Epitopes, T-Lymphocyte , HLA-A Antigens/immunology , Immunity, Cellular , Mutation , SARS-CoV-2 , CD8-Positive T-Lymphocytes/pathology , COVID-19/genetics , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , High-Throughput Nucleotide Sequencing , Humans , Interferon-gamma/immunology , Peptides/genetics , Peptides/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology
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