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1.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321371

ABSTRACT

Background The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial.Methods: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6-minute walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102).Findings: Within 3 months, MSC administration exerted numerical improvement in whole-lung lesion volume compared with the placebo, leading to a significant difference of −10.82% (95% CI: −20.69%, −1.46%, P=0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point, with a significant difference of − 9.02% (95%CI: − 17.44%, − 0.10%, P=0.045) at month 9. More interestingly, 17.86% (10/56) of patients in the MSC group had normal CT images at month 12 ( P= 0.013), but none in the placebo group. The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time, particularly sleep difficulties at month 3 (OR 0.19, 95% CI 0.07,0.50;P=0.001), and usual activity at month 12 (OR 0.15, 95% CI 0.03,0.79;P=0.018). Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.55%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups.Interpretation: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients.Trial Registration: This trial was registered with ClinicalTrials.gov (NCT04288102).Funding The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Ethics Committee of the Fifth Medical Center, Chinese PLA General Hospital (2020-013-D).

2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-321366

ABSTRACT

Background: Treatment of severe Corona Virus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC‑MSCs) to treat patients with severe COVID-19 with lung damage, based on our phase 1 data.Methods: In this randomised, double-blind, and placebo-controlled trial, we recruited 101 eligible patients with severe COVID-19 with lung damage aged between 18–74 years from two hospitals. Enrolled patients were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. We excluded patients with malignant tumours, shock, or other organ failure. The primary endpoint was an altered proportion of whole lung lesion areas from baseline to day 28, measured by chest computed tomography. Other imaging outcomes, 6-minute walk test, maximum vital capacity, diffusing capacity, plasma biomarkers, and adverse events were recorded and analysed. Primary analysis was done in the modified intention-to-treat (mITT) population and safety analysis was done in all patients who started their assigned treatment. Findings: From March 5, 2020, to March 28, 2020, 100 patients were finally enrolled and received either UC-MSCs (n = 65) or placebo (n = 35). During follow-up, the patients receiving UC-MSCs exhibited a trend of numerical improvement in whole lung lesions from baseline to day 28 compared with the placebo cases. UC-MSCs administration significantly reduced the proportions of consolidation lesions from baseline to day 28 in the treated patients compared with the placebo subjects. The 6-minute walk test showed an increased distance in patients treated with UC-MSCs. Notably, UC-MSCs delivery was well tolerated, with no serious adverse events.Interpretation: UC-MSCs treatment is a safe and potentially effective therapeutic approach for patients with severe COVID‑19. The trial suggests that UC-MSCs administration might benefit patients with COVID-19 with lung damage at the convalescent stage as well as the progression stage.Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT04288102.Funding Statement: This trial was supported by The National Key R&D Program of China (2020YFC0841900, 2020YFC0844000, 2020YFC08860900);The Innovation Groups of the National Natural Science Foundation of China (81721002);The National Science and Technology Major Project (2017YFA0105703).Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: Ethical approval was obtained from the institutional review boards of each participating hospital. Written informed consent was obtained from all the enrolled patients or their legal representatives if they were unable to provide consent.

3.
EBioMedicine ; 75: 103789, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1587925

ABSTRACT

BACKGROUND: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. METHODS: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). FINDINGS: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of -10.8% (95% CI: -20.7%, -1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. INTERPRETATION: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. FUNDING: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Aged , Allografts , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Patient Acuity
4.
Nat Metab ; 3(7): 909-922, 2021 07.
Article in English | MEDLINE | ID: covidwho-1279905

ABSTRACT

Exosomes represent a subtype of extracellular vesicle that is released through retrograde transport and fusion of multivesicular bodies with the plasma membrane1. Although no perfect methodologies currently exist for the high-throughput, unbiased isolation of pure plasma exosomes2,3, investigation of exosome-enriched plasma fractions of extracellular vesicles can confer a glimpse into the endocytic pathway on a systems level. Here we conduct high-coverage lipidomics with an emphasis on sterols and oxysterols, and proteomic analyses of exosome-enriched extracellular vesicles (EVs hereafter) from patients at different temporal stages of COVID-19, including the presymptomatic, hyperinflammatory, resolution and convalescent phases. Our study highlights dysregulated raft lipid metabolism that underlies changes in EV lipid membrane anisotropy that alter the exosomal localization of presenilin-1 (PS-1) in the hyperinflammatory phase. We also show in vitro that EVs from different temporal phases trigger distinct metabolic and transcriptional responses in recipient cells, including in alveolar epithelial cells, which denote the primary site of infection, and liver hepatocytes, which represent a distal secondary site. In comparison to the hyperinflammatory phase, EVs from the resolution phase induce opposing effects on eukaryotic translation and Notch signalling. Our results provide insights into cellular lipid metabolism and inter-tissue crosstalk at different stages of COVID-19 and are a resource to increase our understanding of metabolic dysregulation in COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Extracellular Vesicles/metabolism , Lipidomics , Metabolomics , SARS-CoV-2 , Biological Transport , COVID-19/epidemiology , Cell Fractionation , Cell Membrane/metabolism , Chemical Fractionation , Cluster Analysis , Computational Biology/methods , Exosomes/metabolism , Host-Pathogen Interactions , Humans , Lipidomics/methods , Metabolome , Metabolomics/methods , Retrospective Studies , SARS-CoV-2/genetics , SARS-CoV-2/immunology
5.
Clin Infect Dis ; 71(16): 2066-2072, 2020 11 19.
Article in English | MEDLINE | ID: covidwho-1153154

ABSTRACT

BACKGROUND: Thousands of medical staff have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with hundreds of deaths reported. Such loss could be prevented if there were a serologic assay for SARS-CoV-2-specific antibodies for serological surveillance of its infection at the early stage of disease. METHODS: Using Chinese hamster ovarian (CHO) cell-expressed full-length SARS-CoV-2 S1 protein as capturing antigen, a coronavirus disease 2019 (COVID-19)/SARS-CoV-2 S1 serology enzyme-linked immunosorbent assay (ELISA) kit was developed and validated with negative samples collected prior to the outbreak or during the outbreak and positive samples from patients confirmed with COVID-19. RESULTS: The specificity of the ELISA kit was 97.5%, as examined against total 412 normal human samples. The sensitivity was 97.1% by testing against 69 samples from hospitalized and/or recovered COVID-19 patients. The overall accuracy rate reached 97.3%. The assay was able to detect SARS-CoV-2 antibody on day 1 after the onset of COVID-19 disease. The average antibody levels increased during hospitalization and 14 days after discharge. SARS-CoV-2 antibodies were detected in 28 of 276 asymptomatic medical staff and 1 of 5 nucleic acid test-negative "close contacts" of COVID-19 patients. CONCLUSIONS: With the assays developed here, we can screen medical staff, incoming patients, passengers, and people who are in close contact with the confirmed patients to identify the "innocent viral spreaders," protect the medical staff, and stop further spread of the virus.


Subject(s)
Antibodies, Viral/blood , COVID-19/blood , COVID-19/epidemiology , Animals , CHO Cells , COVID-19/virology , Cricetulus , Enzyme-Linked Immunosorbent Assay , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Serologic Tests
6.
Signal Transduct Target Ther ; 6(1): 58, 2021 02 10.
Article in English | MEDLINE | ID: covidwho-1078577

ABSTRACT

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , SARS-CoV-2 , Umbilical Cord , Aged , Allografts , COVID-19/mortality , COVID-19/physiopathology , Double-Blind Method , Female , Humans , Male , Middle Aged , Treatment Outcome
8.
Signal Transduct Target Ther ; 5(1): 172, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-733534

ABSTRACT

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Cord Blood Stem Cell Transplantation/methods , Coronavirus Infections/therapy , Hematopoietic Stem Cells/virology , Mesenchymal Stem Cell Transplantation/methods , Pneumonia, Viral/therapy , Adult , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Drug Combinations , Female , Glucocorticoids/therapeutic use , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Lopinavir , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiration, Artificial , Ritonavir , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
9.
Nat Immunol ; 21(9): 1107-1118, 2020 09.
Article in English | MEDLINE | ID: covidwho-710376

ABSTRACT

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Betacoronavirus/immunology , Coronavirus Infections/immunology , Interferon Type I/metabolism , Pneumonia, Viral/immunology , Receptors, Immunologic/metabolism , Adolescent , Adult , Aged , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/genetics , Antigens, Differentiation, T-Lymphocyte/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19 , Cohort Studies , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunology , GPI-Linked Proteins/metabolism , Humans , Interferon Type I/genetics , Interferon Type I/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , RNA-Seq , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , SARS-CoV-2 , Severity of Illness Index , Single-Cell Analysis
10.
Nat Commun ; 11(1): 3410, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-635899

ABSTRACT

COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Adult , Aged , Aged, 80 and over , Betacoronavirus/immunology , Biomarkers/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , COVID-19 , Chemotaxis, Leukocyte , China/epidemiology , Coronavirus Infections/blood , Coronavirus Infections/virology , Cytokines/blood , Female , Humans , Inflammation , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Leukocyte Count , Lung/immunology , Lung/virology , Lymphocyte Activation , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/virology , SARS-CoV-2
11.
Cell Metab ; 32(2): 188-202.e5, 2020 08 04.
Article in English | MEDLINE | ID: covidwho-612608

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.


Subject(s)
Coronavirus Infections/blood , Coronavirus Infections/pathology , Exosomes/metabolism , G(M3) Ganglioside/blood , Gangliosides/blood , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Adult , Aged , Betacoronavirus , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , COVID-19 , Diglycerides/blood , Female , Humans , Male , Metabolome/physiology , Metabolomics/methods , Middle Aged , Pandemics , SARS-CoV-2 , Sphingomyelins/blood , Tandem Mass Spectrometry , Young Adult
12.
Cell Death Differ ; 27(11): 3196-3207, 2020 11.
Article in English | MEDLINE | ID: covidwho-591591

ABSTRACT

SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-ß, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-ß and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Lymphocyte Activation/immunology , Myeloid-Derived Suppressor Cells/cytology , Pneumonia, Viral/virology , Adult , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , COVID-19 , Coronavirus Infections/immunology , Cytokines/metabolism , Disease Progression , Female , Humans , Inflammation/immunology , Myeloid-Derived Suppressor Cells/immunology , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2
13.
Nature ; 584(7819): 120-124, 2020 08.
Article in English | MEDLINE | ID: covidwho-381744

ABSTRACT

An outbreak of coronavirus disease 2019 (COVID-19)1-3, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)4, has spread globally. Countermeasures are needed to treat and prevent further dissemination of the virus. Here we report the isolation of two specific human monoclonal antibodies (termed CA1 and CB6) from a patient convalescing from COVID-19. CA1 and CB6 demonstrated potent SARS-CoV-2-specific neutralization activity in vitro. In addition, CB6 inhibited infection with SARS-CoV-2 in rhesus monkeys in both prophylactic and treatment settings. We also performed structural studies, which revealed that CB6 recognizes an epitope that overlaps with angiotensin-converting enzyme 2 (ACE2)-binding sites in the SARS-CoV-2 receptor-binding domain, and thereby interferes with virus-receptor interactions by both steric hindrance and direct competition for interface residues. Our results suggest that CB6 deserves further study as a candidate for translation to the clinic.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/chemistry , Antibodies, Viral/pharmacology , Betacoronavirus/chemistry , Binding, Competitive , COVID-19 , Cell Line , Chlorocebus aethiops , Crystallization , Crystallography, X-Ray , Female , Humans , In Vitro Techniques , Macaca mulatta/immunology , Macaca mulatta/virology , Male , Models, Molecular , Neutralization Tests , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Protein Binding/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Viral Load/immunology
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