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1.
Cell ; 184(5): 1201-1213.e14, 2021 03 04.
Article in English | MEDLINE | ID: mdl-33571429

ABSTRACT

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.


Subject(s)
B-Lymphocytes/immunology , COVID-19/immunology , Immunologic Memory , Adult , COVID-19/physiopathology , Flow Cytometry , Germinal Center/cytology , Humans , Lymphocyte Activation , Middle Aged , Severity of Illness Index , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/chemistry
2.
Immunity ; 56(9): 2137-2151.e7, 2023 09 12.
Article in English | MEDLINE | ID: mdl-37543032

ABSTRACT

How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after SARS-CoV-2 Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of the COVID-19 mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limited de novo response against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reactions, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with a marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , SARS-CoV-2 , Memory B Cells , Breakthrough Infections , Epitopes , Antibodies, Viral , Antibodies, Neutralizing
3.
Immunity ; 55(6): 1096-1104.e4, 2022 06 14.
Article in English | MEDLINE | ID: mdl-35483354

ABSTRACT

The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , Memory B Cells , RNA, Messenger/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination
4.
Immunity ; 54(12): 2893-2907.e5, 2021 12 14.
Article in English | MEDLINE | ID: mdl-34614412

ABSTRACT

In addition to serum immunoglobulins, memory B cell (MBC) generation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another layer of immune protection, but the quality of MBC responses in naive and coronavirus disease 2019 (COVID-19)-recovered individuals after vaccination remains ill defined. We studied longitudinal cohorts of naive and disease-recovered individuals for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of antibody repertoires, affinity, and neutralization against variants of concern (VOCs) using unbiased cultures of 2,452 MBCs. Upon boosting, the MBC pool of recovered individuals expanded selectively, matured further, and harbored potent neutralizers against VOCs. Although naive individuals had weaker neutralizing serum responses, half of their RBD-specific MBCs displayed high affinity toward multiple VOCs, including delta (B.1.617.2), and one-third retained neutralizing potency against beta (B.1.351). Our data suggest that an additional challenge in naive vaccinees could recall such affinity-matured MBCs and allow them to respond efficiently to VOCs.


Subject(s)
BNT162 Vaccine/immunology , COVID-19/immunology , Memory B Cells/immunology , Precursor Cells, B-Lymphoid/immunology , RNA, Messenger/genetics , SARS-CoV-2/physiology , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Antibody Affinity , Cells, Cultured , Convalescence , Humans , Immunization, Secondary , Immunologic Memory , Mass Vaccination , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
5.
Blood ; 141(23): 2867-2877, 2023 06 08.
Article in English | MEDLINE | ID: mdl-36893453

ABSTRACT

Sustained response off treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in immune thrombocytopenia (ITP). This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response (CR) on TPO-RAs. The primary end point was the proportion of patients achieving SROT (platelet count >30 × 109/L and no bleeding) at week 24 (W24) with no other ITP-specific medications. Secondary end points included the proportion of sustained CR off-treatment (SCROT, platelet count >100 × 109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with a median age of 58.5 years; 30 of 48 had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27 of 48 achieved SROT, 15 of 48 achieved SCROT at W24; 25 of 48 achieved SROT, and 14 of 48 achieved SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients rechallenged with TPO-RA, 11 of 12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA sequencing revealed enrichment of a tumor necrosis factor α signaling via NF-κB signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based on progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03119974.


Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Adult , Humans , Middle Aged , Prospective Studies , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Platelet Count , Thrombocytopenia/drug therapy , Autoimmunity , Thrombopoietin/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Receptors, Fc/therapeutic use , Hydrazines/therapeutic use
6.
Haematologica ; 106(9): 2449-2457, 2021 09 01.
Article in English | MEDLINE | ID: mdl-32817288

ABSTRACT

B-cell activating factor may be involved in the failure of B-cell depleting therapy with rituximab in immune thrombocytopenia (ITP) by promoting the emergence of splenic long-lived plasma cells. From results obtained in mouse models, we hypothesized that combining rituximab with sequential injections of belimumab could increase the rate of response at one year in patients with persistent or chronic ITP by preventing the emergence of these long-lived plasma cells. The study was a single-center, single arm, prospective phase 2b trial (RITUX-PLUS, NCT03154385) investigating the safety and efficacy of rituximab given at a fixed dose of 1,000 mg, two weeks apart, combined with five infusions of belimumab, 10 mg/kg at week 0 (W0)+2 days, W2+2 days, W4, W8 and W12 for adults with primary persistent or chronic ITP. The primary endpoint was the total number of patients achieving an overall response (complete response + response) at W52 according to a standard definition. In total, 15 non-splenectomized adults, nine (60%) with persistent IPT and six (40%) with chronic ITP, were included. No severe adverse event, infection, or severe hypogammaglobulinemia was observed. Thirteen patients achieved an initial overall response. At W52, 12 (80%) patients achieved an overall response, including ten (66.7%) with complete response. When compared with a cohort of patients receiving rituximab alone, the kinetics of B-cell repopulation appeared similar, but the number of circulating T follicular helper cells was significantly decreased with belimumab combination therapy. Combining rituximab and belimumab seems a promising strategy in ITP, with high efficacy and acceptable safety.


Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Adult , Animals , Antibodies, Monoclonal, Humanized , Humans , Mice , Prospective Studies , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Rituximab/adverse effects , Treatment Outcome
7.
Ann Hematol ; 98(10): 2299-2302, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31444663

ABSTRACT

Iron deficiency anemia (IDA) is often associated with mild to moderate thrombocytosis, and iron deficiency-associated thrombocytopenia (IDAT) is much more uncommon and often misdiagnosed as immune thrombocytopenia (ITP). To better describe the features of IDAT, we conducted a retrospective multicenter case-control study. We identified 10 patients (9 women) with a definite diagnosis IDAT, with a median age of 43.5 [range, 16-72] years and a median platelet count of 30.5 × 109/L [range, 21-80], and 7 patients with a possible diagnosis of IDAT. Bleeding manifestations were absent in all patients but one. All the patients recovered (platelet count ≥ 150 × 109/L) upon iron therapy ± red blood cell transfusion after a median time of 6 [4-39] days. When compared with 30 randomly newly diagnosed ITP patients matched on age, the baseline platelet count was significantly lower in ITP (median = 7 × 109/L [4-59], p < 0.001) whereas MPV was higher (10.5 fL [9,4-13,8] vs 8.2 fL, for IDAT p < 0.001). The median platelet count on day 7 was 337 × 109/L [113-1000] for IDAT cases vs 72 × 109/L [13-212] for ITP controls (p < 0.001). IDAT is potentially an under-recognized cause of thrombocytopenia that may be easily managed with iron therapy.


Subject(s)
Anemia, Iron-Deficiency , Thrombocytopenia , Adolescent , Adult , Age Factors , Aged , Anemia, Iron-Deficiency/blood , Anemia, Iron-Deficiency/complications , Anemia, Iron-Deficiency/diagnosis , Anemia, Iron-Deficiency/epidemiology , Diagnostic Errors , Female , Humans , Male , Middle Aged , Platelet Count , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/epidemiology , Purpura, Thrombocytopenic, Idiopathic/etiology , Retrospective Studies , Thrombocytopenia/blood , Thrombocytopenia/diagnosis , Thrombocytopenia/epidemiology , Thrombocytopenia/etiology
10.
Br J Haematol ; 166(6): 929-35, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24957165

ABSTRACT

In women with pre-existing immune thrombocytopenic purpura (ITP), the effect of pregnancy on the course of the disease is poorly known. We performed a dual-centre retrospective cohort study of 118 pregnancies in 82 women with primary ITP. In early pregnancy, the platelet count was <100 × 10(9) /l in 35·6% of pregnancies. During pregnancy the median platelet count nadir was 66 × 10(9) /l (25th-75th percentile: 42-117), with platelet count <30 × 10(9) /l for 26 pregnancies (22%). In 49% of pregnancies, a significant decrease of the platelet count required treatment at least transiently in preparation for delivery. At the time of delivery, the median platelet count was 110 × 10(9) /l (77-155). Compared to before pregnancy, at 3 months post-partum, only 11% of pregnancies [95% confidence interval (95% CI): 6·8-20·2] showed disease worsening. Previous splenectomy was the only factor significantly associated with ITP worsening after pregnancy (53·9% vs. 10·3%, P < 0·001). For 8·3% of the pregnancies (95% CI: 3·8-15·1), neonatal thrombocytopenia required treatment, especially in case of previous maternal splenectomy (adjusted odds ratio 16·7, 95% CI: 2·61-106). The overall risk of exacerbation of ITP and severe thrombocytopenia during pregnancy is acceptable.


Subject(s)
Pregnancy Complications, Hematologic/blood , Purpura, Thrombocytopenic, Idiopathic/blood , Adult , Delivery, Obstetric , Female , Humans , Platelet Count , Postpartum Hemorrhage/blood , Postpartum Hemorrhage/etiology , Pregnancy , Pregnancy Complications, Hematologic/therapy , Pregnancy Outcome , Prenatal Care , Purpura, Thrombocytopenic, Idiopathic/therapy , Retrospective Studies , Thrombocytopenia, Neonatal Alloimmune/blood , Thrombocytopenia, Neonatal Alloimmune/etiology , Young Adult
12.
Ann Hematol ; 93(2): 309-15, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23912633

ABSTRACT

Immune thrombocytopenia (ITP) results in part from the presence of platelet antibodies, which can be demonstrated by the Monoclonal Antibody-Specific Immobilization of Platelet Antigens (MAIPA) assay. The aim of our study was to correlate the presence of antiplatelet autoantibodies and the natural history of ITP. We performed a retrospective, single-center study of 108 adults with newly diagnosed ITP who had indirect MAIPA assay performed at disease onset. Chronic ITP was defined by the presence of thrombocytopenia after 1 year. Bleeding diathesis was evaluated with a bleeding score. At baseline, patients with a positive indirect MAIPA have a greater bleeding score than patients with negative MAIPA assay [median (interquartile) = 8 (6-12) vs 2 (0-6), p = 0.002]. Patients with a positive indirect MAIPA also had a higher rate of chronic ITP (92.9 vs 68.7 %, p = 0.06). In multivariate analysis, a positive indirect MAIPA result and a platelet count at onset ≥10 × 10(9)/L remained independently associated with chronic ITP [adjusted OR (aOR) = 8.01; 95 % confidence interval (CI), 0.98-66.6; p = 0.05 and aOR = 3.09; 95 % CI, 1.18-8.10; p = 0.02, respectively]. Furthermore, when we analyzed together the results of direct (n = 41) and indirect MAIPA, the same results were observed. Thus, indirect MAIPA positivity at disease onset is associated with more severe hemorrhage and predicts a chronic course in adult ITP patients. MAIPA assay could be useful in the management of ITP patients when it is performed at diagnosis.


Subject(s)
Autoantibodies/blood , Blood Platelets , Hemorrhage , Purpura, Thrombocytopenic, Idiopathic , Adult , Aged , Chronic Disease , Female , Hemorrhage/blood , Hemorrhage/diagnosis , Hemorrhage/etiology , Hep G2 Cells , Humans , Immunosorbent Techniques , Male , Middle Aged , Prospective Studies , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/complications , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Retrospective Studies , Risk Factors
13.
Am J Hematol ; 89(9): E150-5, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24847759

ABSTRACT

Warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease with poorly known natural history and management remaining mainly empirical. To better describe the characteristics and outcome of wAIHA in adults, we performed a single-center cohort study of patients diagnosed with wAIIHA from 2001 to 2012 in our center. Sixty patients (50% women) were included, the mean age at the time of wAIHA onset was 54 ± 23 years. wAIHA was considered "primary" for 21 patients (35%) and was associated with an underlying disorder in 39 (65%), including mainly lymphoproliferative disorders and systemic lupus. All patients but two needed treatment and received corticosteroids, with an overall initial response rate of 87%. However, 63% of the patients were corticosteroid-dependent and 56% required at least one second-line treatment including mainly rituximab (n = 19). At the time of analysis, after a mean follow-up of 46 months, 28 patients (47%) were in remission and off treatment and 5 (8%) had died. The presence of an underlying lymphoproliferative disorder was associated with reduced response to corticosteroids and increased need for second-line therapy. In conclusion, in the last decade and compared to a previous series from our center, the rate of secondary wAIHA has increased and the use of rituximab has emerged as the preferred second-line treatment and corticosteroid-sparing strategy; the overall mortality has significantly decreased (8 vs. 18%).


Subject(s)
Anemia, Hemolytic, Autoimmune/drug therapy , Anemia, Hemolytic, Autoimmune/etiology , Anemia, Hemolytic, Autoimmune/immunology , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Glucocorticoids/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Anemia, Hemolytic, Autoimmune/mortality , Cohort Studies , Disease-Free Survival , Erythrocyte Transfusion , Female , Hemoglobins/analysis , Humans , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/mortality , Lymphoproliferative Disorders/complications , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/immunology , Lymphoproliferative Disorders/mortality , Male , Middle Aged , Rituximab , Splenectomy , Treatment Outcome , Young Adult
14.
Am J Hematol ; 89(2): 194-8, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24254965

ABSTRACT

Treatment of patients with lupus-associated thrombocytopenia (SLE-ITP) is not standardized. We report data on efficacy and safety of hydroxychloroquine (HCQ) in this setting and in ITP patients with positive antinuclear antibodies (ANA) without definite SLE. Inclusion criteria were: definite diagnosis of ITP with a platelet count (PLT) <50 × 10(9) /L, ANA ≥ 1/160 on Hep2 cells with or without a definite diagnosis of SLE, and no sustained response to at least one previous treatment-line and treatment with HCQ. Response criteria were Complete Response (CR) for PLT ≥ 100 × 10(9) /L and Response (R) for PLT ≥30 × 10(9) /L and at least twice the initial value. Forty patients (32 females) with a mean age of 35 ± 17 years and PLT at ITP diagnosis of 14 ± 13 × 10(9) /L were analyzed. Twelve (30%) patients had a SLE-ITP, 28 patients had only positive ANA. All the patients failed to respond to oral prednisone with a median of two treatment-lines (1-5) before HCQ which was initially given in combination with another ITP treatment in 36 patients. Overall response rate was 60% (24/40) including 18 lasting CR and six lasting R maintained with a median follow-up of 64 months (6-146), in ¾ of cases with only HCQ and no concomitant ITP treatment. The response rate (CR+R) was higher in the SLE group vs ANA-positive group (83% vs 50%, P < 0.05). No patient stopped HCQ because of a side-effect. HCQ appears to be a safe and effective second line treatment for patients with SLE-ITP or ITP and high titer of ANA. This trial was registered at www.clinicaltrials.gov as # NCT01549184.


Subject(s)
Antibodies, Antinuclear/immunology , Antirheumatic Agents/therapeutic use , Hydroxychloroquine/therapeutic use , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/immunology , Adolescent , Adult , Antibodies, Antinuclear/blood , Female , Humans , Lupus Erythematosus, Systemic/complications , Male , Middle Aged , Purpura, Thrombocytopenic, Idiopathic/complications , Treatment Outcome , Young Adult
15.
Blood ; 118(16): 4338-45, 2011 Oct 20.
Article in English | MEDLINE | ID: mdl-21832276

ABSTRACT

Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 10(9)/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 10(9)/L (interquartile range, 75-167 × 10(9)/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 10(9)/L (interquartile range, 35-44 × 10(9)/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.


Subject(s)
Purpura, Thrombocytopenic, Idiopathic/drug therapy , Receptors, Fc/therapeutic use , Receptors, Thrombopoietin/agonists , Recombinant Fusion Proteins/therapeutic use , Thrombopoietin/therapeutic use , Adult , Aged , Aged, 80 and over , Blood Platelets/drug effects , Compassionate Use Trials , Female , Humans , Male , Middle Aged , Platelet Count , Recombinant Fusion Proteins/adverse effects , Retrospective Studies , Thrombopoietin/adverse effects , Treatment Outcome , Young Adult
17.
Haematologica ; 98(6): 881-7, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23445876

ABSTRACT

Romiplostim and eltrombopag, the first thrombopoietic receptor-agonists with demonstrated efficacy against immune thrombocytopenia in prospective controlled studies, were recently authorized in most countries for adults with chronic immune thrombocytopenia. So far, no data are available about the potential contribution of switching from romiplostim to eltrombopag or vice versa in terms of efficacy or tolerance. Efficacies and tolerance profiles were evaluated for 46 patients who sequentially received both drugs, switching from one to the other. The reasons for switching were: lack of efficacy for 23 patients, platelet-count fluctuations for 11, side effects for 4, and 8 patients' preferences. For 50-80% of the patients, switching from romiplostim to eltrombopag or eltrombopag to romiplostim effectively impacted the platelet count, with fluctuations disappearing in 54% and side effects resolved in 100%. In 80% of the patients, the 2 thrombopoietic receptor-agonists achieved similar response patterns. Our results confirmed that switching from one thrombopoietic receptor-agonist to the other could be beneficial in clinical practice for patients with severe chronic immune thrombopenia who failed to respond or experienced adverse events to the first. (Clinical Trials.gov identifier: NCT01618734).


Subject(s)
Benzoates/therapeutic use , Hydrazines/therapeutic use , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Pyrazoles/therapeutic use , Receptors, Fc/therapeutic use , Receptors, Thrombopoietin/agonists , Recombinant Fusion Proteins/therapeutic use , Thrombopoietin/therapeutic use , Adult , Aged , Aged, 80 and over , Benzoates/administration & dosage , Benzoates/adverse effects , Drug Substitution , Female , Humans , Hydrazines/administration & dosage , Hydrazines/adverse effects , Male , Middle Aged , Pilot Projects , Platelet Count , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Receptors, Fc/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Retrospective Studies , Thrombopoietin/administration & dosage , Thrombopoietin/adverse effects , Treatment Outcome
19.
JCI Insight ; 8(13)2023 07 10.
Article in English | MEDLINE | ID: mdl-37252802

ABSTRACT

SARS-CoV-2 mRNA vaccination generates protective B cell responses targeting the SARS-CoV-2 spike glycoprotein. Whereas anti-spike memory B cell responses are long lasting, the anti-spike humoral antibody response progressively wanes, making booster vaccinations necessary for maintaining protective immunity. Here, we qualitatively investigated the plasmablast responses by measuring from single cells within hours of sampling the affinity of their secreted antibody for the SARS-CoV-2 spike receptor binding domain (RBD) in cohorts of BNT162b2-vaccinated naive and COVID-19-recovered individuals. Using a droplet microfluidic and imaging approach, we analyzed more than 4,000 single IgG-secreting cells, revealing high interindividual variability in affinity for RBD, with variations over 4 logs. High-affinity plasmablasts were induced by BNT162b2 vaccination against Hu-1 and Omicron RBD but disappeared quickly thereafter, whereas low-affinity plasmablasts represented more than 65% of the plasmablast response at all time points. Our droplet-based method thus proves efficient at fast and qualitative immune monitoring and should be helpful for optimization of vaccination protocols.


Subject(s)
BNT162 Vaccine , COVID-19 , Humans , SARS-CoV-2/genetics , Microfluidics , COVID-19/prevention & control , RNA, Messenger
20.
J Exp Med ; 220(1)2023 01 02.
Article in English | MEDLINE | ID: mdl-36342455

ABSTRACT

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.


Subject(s)
B-Lymphocytes , COVID-19 Vaccines , COVID-19 , Interferon Type I , Humans , Antibodies, Neutralizing , Antibodies, Viral , Autoantibodies , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Toll-Like Receptor 7/genetics , Vaccination , mRNA Vaccines , COVID-19 Vaccines/immunology , B-Lymphocytes/immunology , Interferon Type I/deficiency
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