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1.
Int J Mol Sci ; 23(14)2022 Jul 12.
Article in English | MEDLINE | ID: covidwho-1964003

ABSTRACT

The mosquito-borne disease caused by the Rocio virus is a neglected threat, and new immune inputs for serological testing are urgently required for diagnosis in low-resource settings and epidemiological surveillance. We used in silico approaches to identify a specific antigenic peptide (p_ROCV2) in the NS1 protein of the Rocio virus that was theoretically predicted to be stable and exposed on its surface, where it demonstrated key properties allowing it to interact with antibodies. These findings related to the molecular dynamics of this peptide provide important insights for advancing diagnostic platforms and investigating therapeutic alternatives.


Subject(s)
Flavivirus , Molecular Dynamics Simulation , Animals , Immunologic Tests , Molecular Docking Simulation , Peptides , Viral Nonstructural Proteins/chemistry
2.
In Silico Pharmacol ; 10(1): 12, 2022.
Article in English | MEDLINE | ID: covidwho-1959193

ABSTRACT

Despite the availability of COVID-19 vaccines, additional more potent vaccines are still required against the emerging variations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the present investigation, we have identified a promising vaccine candidate against the Omicron (B.1.1.529) using immunoinformatics approaches. Various available tools like, the Immune Epitope Database server resource, and NetCTL-1.2, have been used for the identification of the promising T-cell and B-cell epitopes. The molecular docking was performed to check the interaction of TLR-3 receptors and validated 3D model of vaccine candidate. The codon optimization was done followed by cloning using SnapGene. Finally, In-silico immune simulation profile was also checked. The identified T-cell and B-cell epitopes have been selected based on their antigenicity (VaxiJen v2.0) and, allergenicity (AllerTOP v2.0). The identified epitopes with antigenic and non-allergenic properties were fused with the specific peptide linkers. In addition, the 3D model was constructed by the PHYRE2 server and validated using ProSA-web. The validated 3D model was further docked with the Toll-like receptor 3 (TLR3) and showed good interaction with the amino acids which indicate a promising vaccine candidate against the Omicron variant of SARS-CoV-2. Finally, the codon optimization, In-silico cloning and immune simulation profile was found to be satisfactory. Overall, the designed vaccine candidate has a potential against variant of SARS-Cov-2. However, further experimental studies are required to confirm.

3.
FEBS Open Bio ; 2022 Jul 22.
Article in English | MEDLINE | ID: covidwho-1958661

ABSTRACT

B cells recognize antigens via membrane-expressed B-cell receptors (BCR) and antibodies. Similar human BCR sequences are frequently found at a significantly higher frequency than that theoretically calculated. Patients infected with SARS-CoV2 and HIV or with autoimmune diseases share very similar BCRs. Therefore, in silico reconstitution of BCR repertoires and identification of stereotypical BCR sequences related to human pathology have diagnostic potential. Furthermore, monitoring changes of clinically significant BCR sequences and isotype conversion has prognostic potential. For BCR repertoire analysis, peripheral blood (PB) is the most convenient source. However, the optimal human PB volume for in silico reconstitution of the BCR repertoire has not been studied in detail. Here, we sampled 5, 10, and 20 mL PB from the left arm and 40 mL PB from the right arm of two volunteers, reconstituted in silico PB BCR repertoires, and compared their composition. In both volunteers, PB sampling over 20 mL resulted in slight increases in functional unique sequences (FUSs) or almost no increase in repertoire diversity. All FUSs with a frequency above 0.08% or 0.03% in the 40 mL PB BCR repertoire were detected even in the 5 mL PB BCR repertoire from each volunteer. FUSs with a higher frequency were more likely to be found in BCR repertoires from reduced PB volume, and those coexisting in two repertoires showed a statistically significant correlation in frequency irrespective of sampled anatomical site. The correlation was more significant in higher-frequency FUSs. These observations support the potential of BCR repertoire analysis for diagnosis.

4.
Vaccines (Basel) ; 10(8)2022 Jul 23.
Article in English | MEDLINE | ID: covidwho-1957469

ABSTRACT

Mucosal surfaces are the first contact sites of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most SARS-CoV-2 vaccines induce specific IgG responses but provide limited mucosal immunity. Cytokine B-cell activation factor (BAFF) and A proliferation-inducing ligand (APRIL) in the tumor necrosis factor (TNF) superfamily play key immunological functions during B cell development and antibody production. Furthermore, homeostatic chemokines, such as C-X-C motif chemokine ligand 13 (CXCL13), chemokine (C-C motif) ligand 19 (CCL19), and CCL21, can induce B- and T-cell responses to infection and promote the formation of inducible bronchus-associated lymphoid tissues (iBALT), where specific local immune responses and memory cells are generated. We reviewed the role of BAFF, APRIL, CXCL13, CCL19, and CCL21 in the activation of local B-cell responses and antibody production, and the formation of iBALT in the lung following viral respiratory infections. We speculate that mucosal vaccines may offer more efficient protection against SARS-CoV-2 infection than systematic vaccines and hypothesize that a novel SARS-CoV-2 mRNA mucosal vaccine using BAFF/APRIL or CXCL13 as immunostimulants combined with the spike protein-encoding mRNA may enhance the efficiency of the local immune response and prevent the early stages of SARS-CoV-2 replication and the rapid viral clearance from the airways.

5.
Front Immunol ; 13: 890943, 2022.
Article in English | MEDLINE | ID: covidwho-1952331

ABSTRACT

B-cell epitopes (BCEs) are a set of specific sites on the surface of an antigen that binds to an antibody produced by B-cell. The recognition of BCEs is a major challenge for drug design and vaccines development. Compared with experimental methods, computational approaches have strong potential for BCEs prediction at much lower cost. Moreover, most of the currently methods focus on using local information around target residue without taking the global information of the whole antigen sequence into consideration. We propose a novel deep leaning method through combing local features and global features for BCEs prediction. In our model, two parallel modules are built to extract local and global features from the antigen separately. For local features, we use Graph Convolutional Networks (GCNs) to capture information of spatial neighbors of a target residue. For global features, Attention-Based Bidirectional Long Short-Term Memory (Att-BLSTM) networks are applied to extract information from the whole antigen sequence. Then the local and global features are combined to predict BCEs. The experiments show that the proposed method achieves superior performance over the state-of-the-art BCEs prediction methods on benchmark datasets. Also, we compare the performance differences between data with or without global features. The experimental results show that global features play an important role in BCEs prediction. Our detailed case study on the BCEs prediction for SARS-Cov-2 receptor binding domain confirms that our method is effective for predicting and clustering true BCEs.


Subject(s)
COVID-19 , Epitopes, B-Lymphocyte , Humans , Protein Binding , SARS-CoV-2
6.
Open Forum Infect Dis ; 9(6): ofac064, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1948416

ABSTRACT

Profoundly B-cell-depleted patients can have prolonged severe acute respiratory syndrome coronavirus 2 infections with evidence of active viral replication, due to inability to mount an adequate humoral response to clear the virus. We present 3 B-cell-depleted patients with prolonged coronavirus disease 2019 infection who were successfully treated with a combination of casirivimab/imdevimab and remdesivir.

7.
IDCases ; 29: e01528, 2022.
Article in English | MEDLINE | ID: covidwho-1945122

ABSTRACT

Background: Patients having undergone B-cell-depletion with anti-CD20-antibodies have a higher risk of mortality, delayed viral clearance and prolonged infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report two cases of patients with persistent coronavirus disease 2019 (COVID-19) in association with B-cell-depletion that were treated with the monoclonal antibody Sotrovimab. Case presentation: Both patients presented with chronic symptoms of COVID-19 such as dyspnea, fatigue, and chest pain. Nasopharyngeal swabs remained positive months after the initial infection with fluctuating cycle threshold (Ct) values around 30. Both patients received a single infusion with the monoclonal SARS-CoV-2 antibody Sotrovimab, which resulted in a rapid improvement of symptoms and inflammation markers as well as negative SARS-CoV-2 swabs. A follow-up after a month showed ongoing improvement of symptoms, persistent negative SARS-CoV-2 swabs, and positive serum antibodies. Conclusion: Infusion with the monoclonal SARS-CoV-2 antibody led to rapid improvement in two patients with persistent COVID-19 after B-cell depletion.

8.
Methods Mol Biol ; 2511: 133-147, 2022.
Article in English | MEDLINE | ID: covidwho-1941372

ABSTRACT

SARS-CoV-2 causes generally mild symptoms, with approximately 10-20% of cases progressing to severe disease. The pathophysiologic mechanisms by which SARS-CoV-2 causes severe disease are largely unknown. Data have indicated the involvement of different immunogenetic markers such as HLA, T, and B cells, to be associated with disease outcome. This has led to interest in these genes as potential biomarkers of SARS-CoV-2 susceptibility and for predicting prognosis and response to vaccines and other therapeutic strategies. In this chapter, we discussed outline protocols for characterizing these potential biomarkers and methods for identifying SARS-CoV-2 biomarkers using the Luminex® 100/200 technology and next-generation sequencing.


Subject(s)
COVID-19 , SARS-CoV-2 , Biomarkers , COVID-19/diagnosis , High-Throughput Nucleotide Sequencing , Humans , Immunogenetics , SARS-CoV-2/genetics
9.
Methods Mol Biol ; 2453: 447-476, 2022.
Article in English | MEDLINE | ID: covidwho-1935747

ABSTRACT

High-throughput sequencing of adaptive immune receptor repertoires (AIRR, i.e., IG and TR ) has revolutionized the ability to study the adaptive immune response via large-scale experiments. Since 2009, AIRR sequencing (AIRR-seq) has been widely applied to survey the immune state of individuals (see "The AIRR Community Guide to Repertoire Analysis" chapter for details). One of the goals of the AIRR Community is to make the resulting AIRR-seq data FAIR (Findable, Accessible, Interoperable, and Reusable) (Wilkinson et al. Sci Data 3:1-9, 2016), with a primary goal of making it easy for the research community to reuse AIRR-seq data (Breden et al. Front Immunol 8:1418, 2017; Scott and Breden. Curr Opin Syst Biol 24:71-77, 2020). The basis for this is the MiAIRR data standard (Rubelt et al. Nat Immunol 18:1274-1278, 2017). For long-term preservation, it is recommended that researchers store their sequence read data in an INSDC repository. At the same time, the AIRR Community has established the AIRR Data Commons (Christley et al. Front Big Data 3:22, 2020), a distributed set of AIRR-compliant repositories that store the critically important annotated AIRR-seq data based on the MiAIRR standard, making the data findable, interoperable, and, because the data are annotated, more valuable in its reuse. Here, we build on the other AIRR Community chapters and illustrate how these principles and standards can be incorporated into AIRR-seq data analysis workflows. We discuss the importance of careful curation of metadata to ensure reproducibility and facilitate data sharing and reuse, and we illustrate how data can be shared via the AIRR Data Commons.


Subject(s)
Information Dissemination , Research Design , High-Throughput Nucleotide Sequencing , Humans , Information Dissemination/methods , Reproducibility of Results , Workflow
10.
Methods Mol Biol ; 2453: 297-316, 2022.
Article in English | MEDLINE | ID: covidwho-1935746

ABSTRACT

Adaptive immune receptor repertoires (AIRRs) are rich with information that can be mined for insights into the workings of the immune system. Gene usage, CDR3 properties, clonal lineage structure, and sequence diversity are all capable of revealing the dynamic immune response to perturbation by disease, vaccination, or other interventions. Here we focus on a conceptual introduction to the many aspects of repertoire analysis and orient the reader toward the uses and advantages of each. Along the way, we note some of the many software tools that have been developed for these investigations and link the ideas discussed to chapters on methods provided elsewhere in this volume.


Subject(s)
Receptors, Immunologic , Software , Receptors, Immunologic/genetics
11.
Cytopathology ; 33(4):426-429, 2022.
Article in English | EMBASE | ID: covidwho-1937919
12.
Cancers (Basel) ; 14(14)2022 Jul 20.
Article in English | MEDLINE | ID: covidwho-1938701

ABSTRACT

Background: Due to B-cell aplasia following CAR-T-cell therapy, patients are at risk of severe SARS-CoV-2 course. Methods: COVID-19 vaccines were assessed by IgG antibody tests against SARS-CoV-2 spike protein (anti-S1/S2). Vaccination procedures: group (1): CAR-T-cells followed by two to four vaccine doses; group (2): Two vaccine doses prior to CAR-T-cells, followed by doses 3 or 4. Results: In group 1 (n = 32), 7/30 patients (23.2%) had positive antibody tests after a second dose, 9/23 (39.1%) after a third dose, and 3/3 patients after a fourth dose. A third dose led to seroconversion in 5 of 21 patients (23.8%) with available data, while a fourth dose did so in 2/3 patients. Higher B-cells (AUC: 96.2%, CI: 89-100, p = 0.0006) and lower CAR-T-cell copies (AUC: 77.3%, CI: 57-97, p = 0.0438) were predictive of positive humoral vaccine response. In group 2 (n = 14), 6/14 patients (42.9%) had a positive antibody test after a second dose, 3/8 patients (37.5%) after a third dose, and 3/4 patients after a fourth dose. A third dose led to seroconversion in 1/8 patients (12.5%), while a fourth dose did so in 3/4 patients. Conclusion: Additional vaccine doses increased seroconversion rates whilst high B-cell counts and low CAR-T-cell copy numbers were associated with positive antibody response.

13.
Viral Immunol ; 35(6): 425-436, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1937640

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has resulted in major worldwide disruption and loss of life over the last 2 years. Many research studies have shown waning serological SARS-CoV-2-specific IgG antibody titers over time, yet, it is unclear whether these changes are reflected in the potential functional reactivation of SARS-CoV-2 antigen-specific memory B cells (MBC) populations. This is especially true in the contexts of differing COVID-19 disease severity and after vaccination regimens. This study aimed to investigate these by polyclonal in vitro reactivation of MBC populations followed by analysis using SAR-CoV-2 antigen-specific B cell ELISpots and IgG antibody ELISAs. Natural disease-associated differences were investigated in 52 donors who have recovered from COVID-19 with varying disease severity, from asymptomatic to severe COVID-19 disease, accompanied by a longitudinal evaluation in a subset of donors. Overall, these data showed limited disease severity-associated differences between donor groups but did show that COVID-19 serologically positive donors had strong antigen-specific MBC-associated responses. MBC responses were better maintained 6 months after recovery from infection when compared to serological antigen-specific IgG antibody titers. A similar investigation after vaccination using 14 donors showed robust serological antigen-specific antibody responses against spike protein that waned over time. MBC-associated responses against spike protein were also observed but showed less waning over time, indicating maintenance of a protective response 6 months after vaccination. Further research is required to evaluate these putatively functional SARS-CoV-2-specific responses in the context of long-term protection mediated by vaccination against this pathogen.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Antibodies, Viral , COVID-19/prevention & control , Humans , Immunoglobulin G , Memory B Cells , SARS-CoV-2 , Vaccination
14.
Expert Rev Anti Infect Ther ; : 1-8, 2022 Jul 22.
Article in English | MEDLINE | ID: covidwho-1937582

ABSTRACT

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell immunotherapy has revolutionized the prognosis of refractory or relapsed B-cell malignancies. CAR-T cell recipients have immunosuppression generated by B-cell aplasia, leading to a higher susceptibility to respiratory virus infections and poor response to vaccination. AREAS COVERED: This review focuses on the challenge posed by B-cell targeted immunotherapies: managing long-lasting B-cell impairment during the successive surges of a deadly viral pandemic. We restricted this report to data regarding vaccine efficacy in CAR-T cell recipients, outcomes after developing COVID-19 and specificities of treatment management. We searched in MEDLINE database to identify relevant studies until 31 March 2022. EXPERT OPINION: Among available observational studies, the pooled mortality rate reached 40% in CAR-T cell recipients infected by SARS-CoV-2. Additionally, vaccine responses seem to be widely impaired in recipients (seroconversion 20%, T-cell response 50%). In this setting of B-cell depletion, passive immunotherapy is the backbone of treatment. Convalescent plasma therapy has proven to be a highly effective curative treatment with rare adverse events. Neutralizing monoclonal antibodies could be used as pre-exposure prophylaxis or early treatment but their neutralizing activity is constantly challenged by new variants. In order to reduce viral replication, direct-acting antiviral drugs should be considered.

15.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927837

ABSTRACT

Introduction: The Fungitell assay is an in vitro diagnostic test for the qualitative detection of (1-3)-beta-D-Glucan (BDG) in serum. It can be particularly useful in early diagnosis of fungal infections that would otherwise take weeks to finalize in culture.Description:This is a case of a 73 year old Filipino female with a history of diffuse large B-cell lymphoma status post RCHOP therapy, currently maintained on Ritixumab, and rheumatoid arthritis treated with Methotrexate who was admitted to the hospital with increasing shortness of breath for several weeks. In the Emergency Department she was hypoxic and required 2 liters of oxygen via nasal cannula and with 92% oxygen saturation. Her vital signs were otherwise normal. She was afebrile and WBC was 9.4. She had a negative respiratory viral PCR which included COVID-19. Infectious work up including sputum culture and urine antigens were also sent. A CT chest was performed and showed bilateral ground glass opacities suspicious for atypical pneumonia.There was concern for drug toxicity from Methotrexate which was subsequently suspended. A bronchoscopy and bronchoalveolar lavage (BAL) was performed to rule out infection prior to starting steroids for suspected pneumonitis. Cell count from the BAL revealed low neutrophils. There was negative growth over the next 48 hours. Steroids were initiated at 1 mg/kg daily and patient was discharged home with close outpatient follow up scheduled. A fungitell (serum beta D glucan) that was collected from the BAL had resulted after the patient was discharged home. The level returned very elevated (>500). The patient was contacted and she reported that her symptoms did not improve with the steroids. She was still requiring up to four liters of oxygen at home. She was asked to return to the hospital to work up an undiagnosed fungal or PJP pneumonia. A repeat bronchoscopy was performed and a PJP PCR was tested on the BAL. This returned positive. She was started on Bactrim for 14 days to treat PJP pneumonia. She was weaned down to 2 liters of oxygen and was doing well from a pulmonary standpoint at her outpatient follow up visit 2 weeks later. Discussion: The Fungitell assay test in this case was crucial to help guide us to the correct diagnosis. In patients who are immunocompromised, physicians should utilize specialty testing such as Fungitell when it is available. Compared to microbial fungal culture, Fungitell results faster, has a higher sensitivity and a higher negative predictive value. (Figure Presented).

16.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927797

ABSTRACT

Rationale: Individuals with COPD who develop COVID-19 are at increased risk of hospitalization, ICU admission and death. COPD is associated with increased airway epithelial expression of ACE2, the receptor mediating SARS-CoV-2 entry into cells. Hypercapnia commonly develops in advanced COPD and is associated with frequent and potentially fatal pulmonary infections. We previously reported that hypercapnia increases viral replication, lung injury and mortality in mice infected with influenza A virus. Also, global gene expression profiling of primary human bronchial epithelial (HBE) cells showed that elevated CO2 upregulates expression of cholesterol biosynthesis genes, including HMGCS1, and downregulates ATP-binding cassette (ABC) transporters that promote cholesterol efflux. Given that cellular cholesterol is important for entry of viruses into cells, in the current study we assessed the impact of hypercapnia on regulation of cellular cholesterol levels, and resultant effects on expression of ACE2 and entry of Pseudo-SARS-CoV-2 in cultured HBE, BEAS-2B and VERO cells, and airway epithelium of mice. Methods: Differentiated HBE, BEAS-2B or VERO cells were pre-incubated in normocapnia (5% CO2, PCO2 36 mmHg) or hypercapnia (15% CO2, PCO2 108 mmHg), both with normoxia, for 4 days. Expression of ACE2 and sterol regulatory element binding protein 2 (SREPB2), the master regulator of cholesterol synthesis, was assessed by immunoblot or immunofluorescence. Cholesterol was measured in cell lysates by Amplex red assay. Cells cultured in normocapnia or hypercapnia were also infected with Pseudo SARS-CoV-2, a Neon Green reporter baculovirus. For in vivo studies, C57BL/6 mice were exposed to normoxic hypercapnia (10% CO2/21% O2) for 7 days, or air as control, and airway epithelial expression of ACE2, SREBP2, ABCA1, ABCG1 and HMGCS1 was assessed by immunofluorescence. SREBP2 was blocked using the small molecules betulin or AM580, and cellular cholesterol was disrupted using MβCD. Results: Hypercapnia increased expression and activation of SREBP2 and decreased expression of ABC transporters, thereby augmenting epithelial cholesterol levels. Elevated CO2 also augmented ACE2 expression and Pseudo-SARSCoV- 2 entry into epithelial cells in vitro and in vivo. These effects were all reversed by blocking SREBP2 or disrupting cellular cholesterol. Conclusion: Hypercapnia augments cellular cholesterol levels by altering expression of cholesterol biosynthetic enzymes and efflux transporters, leading to increased epithelial expression of ACE2 and entry of Pseudo-SARS-CoV-2 into cells. These findings suggest that ventilatory support to limit hypercapnia or pharmacologic interventions to decrease cellular cholesterol might reduce viral burden and improve clinical outcomes of SARSCoV- 2 infection in advanced COPD and other severe lung diseases.

17.
Eur J Neurol ; 2022 Jul 08.
Article in English | MEDLINE | ID: covidwho-1927583

ABSTRACT

BACKGROUND AND PURPOSE: Recent findings document a blunted humoral response to SARS-CoV-2 vaccination in patients on anti-CD20 treatment. Although most patients develop a cellular response, it is still important to identify predictors of seroconversion to optimize vaccine responses. METHODS: We determined antibody responses after SARS-CoV-2 vaccination in a real-world cohort of multiple sclerosis patients (n = 94) treated with anti-CD20, mainly rituximab, with variable treatment duration (median = 2.9, range = 0.4-9.6 years) and time from last anti-CD20 infusion to vaccination (median = 190, range = 60-1032 days). RESULTS: We find that presence of B cells and/or rituximab in blood predict seroconversion better than time since last infusion. Using multiple logistic regression, presence of >0.5% B cells increased probability of seroconversion with an odds ratio (OR) of 5.0 (95% confidence interval [CI] = 1.0-28.1, p = 0.055), whereas the corresponding OR for ≥6 months since last infusion was 1.45 (95% CI = 0.20-10.15, p = 0.705). In contrast, detectable rituximab levels were negatively associated with seroconversion (OR = 0.05, 95% CI = 0.002-0.392, p = 0.012). Furthermore, naïve and memory IgG+ B cells correlated with antibody levels. Although retreatment with rituximab at 4 weeks or more after booster depleted spike-specific B cells, it did not noticeably affect the rate of decline in antibody titers. Interferon-γ and/or interleukin-13 T-cell responses to the spike S1 domain were observed in most patients, but with no correlation to spike antibody levels. CONCLUSIONS: These findings are relevant for providing individualized guidance to patients and planning of vaccination schemes, in turn optimizing benefit-risk with anti-CD20.

18.
J Clin Immunol ; 2022 Jul 09.
Article in English | MEDLINE | ID: covidwho-1926047

ABSTRACT

BACKGROUND AND PURPOSE: Waning immunity and the surge of SARS-CoV-2 variants are responsible for breakthrough infections, i.e., infections in fully vaccinated individuals. Although the majority of vaccinated infected subjects report mild or no symptoms, some others require hospitalization. The clinical and immunological features of vaccinated hospitalized COVID-19 patients are currently unknown. METHODS: Twenty-nine unvaccinated and 36 vaccinated hospitalized COVID-19 patients were prospectively enrolled and clinical and laboratory data were gathered. Immunophenotyping of leukocytes' subsets, T and B cell SARS-CoV-2-specific responses were evaluated via flow cytometry. Anti-IFN-α autoantibodies were measured via ELISA. RESULTS: Despite vaccinated patients were older and with more comorbidities, unvaccinated subjects showed higher levels of pro-inflammatory markers, more severe disease, and increased mortality rate. Accordingly, they presented significant alterations in the circulating leukocyte composition, typical of severe COVID-19. Vaccinated patients displayed higher levels of anti-Spike IgGs and Spike-specific B cells. Of all participants, survivors showed higher levels of anti-Spike IgGs and Spike-specific CD4+ T cells than non-survivors. At hospital admission, 6 out of 65 patients (9.2%) displayed high serum concentrations of autoantibodies targeting IFN-α. Remarkably, 3 were unvaccinated and eventually died, while the other 3 were vaccinated and survived. CONCLUSION: Despite more severe pre-existing clinical conditions, vaccinated patients have good outcome. A rapid activation of anti-SARS-CoV-2-specific immunity is fundamental for the resolution of the infection. Therefore, prior immunization through vaccination provides a significant contribution to prevention of disease worsening and can even overcome the presence of high-risk factors (i.e., older age, comorbidities, anti-IFN-α autoantibodies).

19.
Vox Sanguinis ; 117(SUPPL 1):252, 2022.
Article in English | EMBASE | ID: covidwho-1916332

ABSTRACT

Background: The polymorphic Human Leukocyte Antigens (HLA) play an important role in determining the best matched donor in a haematopoietic stem cell transplant (HSCT). Hence, accurate HLA typing results are crucial to determine the successfulness of a transplant. Most of the patients of hematologic diseases will receive blood transfusion regularly. There is a potential discrepancy result or ambiguous results when a patient already received non-leukoreduced blood component prior to blood sampling for HLA typing. Aims: To determine differences between the HLA typing result from the DNA extracted from blood sample and buccal swab sample. Methods: Blood sample and buccal swab sample were collected from a total of 66 patients with different hematologic diseases and plan to go for haematopoietic stem cell transplant. These patients received at least one pack of red blood cell or platelet between 1 and 14 days prior to blood sample taken. DNA was extracted from all 66 blood samples and 66 buccal swab samples. All samples were typed for six loci (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1) with Next Generation Sequencing (NGS). NGS was performed in all those samples using the NGSgo-MX6-1 kit. After the library preparation by using NGSgo-LibrX ligation reagents and the NGSgoIndX adapter, it was sequenced in iSeq 100. The results were then analysed with NGSengine software. The results for blood sample and buccal swab sample were then compared. Results: Out of 66 patients, 25 patients received either red blood cell or platelet component prior to blood sample taken for HLA typing. One patient received red blood cell and plasma and the others received red blood cell and platelets before the sample was taken. There are no differences between the HLA typing result from the DNA extracted from blood sample or buccal swab sample for all the 66 patients. The sequencing noise level for both DNA extracted from blood and buccal swab was well separated from the alleles as we can see from the base variation plot. Summary/Conclusions: This preliminary study only focus on the adult patients with hematologic diseases (ALL, AML, CML, MDS, multiple myeloma, DLBCL, hemophagocytic lymphohistiocytosis, NKT Cell lymphoma and severe aplastic anaemia) for the past 1 year. From the findings of this study, blood samples from the patient who underwent blood transfusion can be used for HLA typing instead of using buccal swab samples. This will lower the risk of Covid-19 infection among the healthcare worker who performs the buccal swab sampling from the patient with unknown status of Covid-19 infectivity. However, an extensive study with the appropriate number of samples needed to confirm this finding in the near future.

20.
HemaSphere ; 6(SUPPL 2):16-17, 2022.
Article in English | EMBASE | ID: covidwho-1915867

ABSTRACT

G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in healthy human tissue but is highly expressed in malignant plasma cells, making it a promising target for immunotherapy approaches for MM. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to both GPRC5D and CD3 receptors to redirect T cells to kill MM cells. Updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) are reported (NCT03399799). Eligible patients had RRMM or were intolerant to standard therapies. Patients who were previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC;range: 5.0-800 μg/kg) weekly (QW) or biweekly (Q2W) with step-up dosing. The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03;cytokine release syndrome (CRS) was graded per Lee et al 2014 criteria. Responses were investigator-assessed per IMWG criteria. As of July 19, 2021, 95 patients had received SC talquetamab. The original RP2D was 405 μg/kg SC talquetamab QW with step-up doses, and a second RP2D of 800 μg/kg SC talquetamab Q2W with step-up doses was also identified. 30 patients received 405 μg/kg QW (median 61.5 years [range 46-80];63% male;100% triple-class exposed;80% penta-drug exposed;77% triple-class refractory, 20% penta-drug refractory;30% prior BCMA-directed therapy;median follow-up [mF/U]: 7.5 mo [range 0.9-15.2]). 23 patients received 800 μg/kg Q2W (median 60.0 years [range 47-84];48% male;96% triple-class exposed;70% penta-drug exposed;65% triple-class refractory, 22% penta-drug refractory;17% prior BCMA-directed therapy;mF/U: 3.7 mo [range 0.0-12.0]). No treatment discontinuations due to AEs were reported at either RP2Ds. Most common AEs at the 405 μg/kg QW were CRS (73%;1 grade 3 CRS), neutropenia (67%;grade 3/4: 60%), and dysgeusia (60%;grade 2: 29%). Skin-related AEs occurred in 77% of patients and were all grade 1/2 (nail disorders: 30%). Infections occurred in 37% of patients (1 grade 3 COVID-19 pneumonia). Most common AEs at 800 μg/kg Q2W were CRS (78%;all grade 1/2), dry mouth (44%;all grade 1/2), and neutropenia (44%;grade 3/4: 35%). Skin-related AEs occurred in 65% of patients with grade 3 events in 13% (nail disorders: 17%). Infections occurred in 13% of patients (1 grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated at 405 μg/kg QW, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR]: 57%). In 17 response-evaluable patients treated at 800 μg/ kg Q2W, the ORR was 71% (≥VGPR: 53%). Responses were durable and deepened over time with both RP2Ds (Figure). Median duration of response (DOR) was not reached at either RP2D;6-month DOR rate was 67% (95% CI: 41-84) at 405 μg/kg QW. Serum trough levels of talquetamab were comparable at both RP2Ds. Pharmacodynamic data at both RP2Ds showed peripheral T cell activation and induction of cytokines. SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data suggest that less frequent, higher doses of SC talquetamab do not negatively impact the safety profile. Further evaluation of talquetamab as monotherapy (phase 2;NCT04634552) and in combination with other therapies in patients with RRMM is underway. (Figure Presented) .

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