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1.
J Transl Med ; 19(1): 524, 2021 12 30.
Article in English | MEDLINE | ID: covidwho-1623635

ABSTRACT

BACKGROUND: Pronounced sex differences in the susceptibility and response to SARS-CoV-2 infection remain poorly understood. Emerging evidence has highlighted the potential importance of autoimmune activation in modulating the acute response and recovery trajectories following SARS-CoV-2 exposure. Given that immune-inflammatory activity can be sex-biased in the setting of severe COVID-19 illness, the aim of the study was to examine sex-specific autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease. METHODS: In this study, we assessed autoantibody (AAB) reactivity to 91 autoantigens previously linked to a range of classic autoimmune diseases in a cohort of 177 participants (65% women, 35% men, mean age of 35) with confirmed evidence of prior SARS-CoV-2 infection based on presence of antibody to the nucleocapsid protein of SARS-CoV-2. Data were compared to 53 pre-pandemic healthy controls (49% women, 51% men). For each participant, socio-demographic data, serological analyses, SARS-CoV-2 infection status and COVID-19 related symptoms were collected by  an electronic survey of questions. The symptoms burden score was constructed based on the total number of reported symptoms (N = 21) experienced within 6 months prior to the blood draw, wherein a greater number of symptoms corresponded to a higher score and assigned as more severe burden. RESULTS: In multivariable analyses, we observed sex-specific patterns of autoreactivity associated with the presence or absence (as well as timing and clustering of symptoms) associated with prior COVID-19 illness. Whereas the overall AAB response was more prominent in women following asymptomatic infection, the breadth and extent of AAB reactivity was more prominent in men following at least mildly symptomatic infection. Notably, the observed reactivity included distinct antigens with molecular homology with SARS-CoV-2. CONCLUSION: Our results reveal that prior SARS-CoV-2 infection, even in the absence of severe clinical disease, can lead to a broad AAB response that exhibits sex-specific patterns of prevalence and antigen selectivity. Further understanding of the nature of triggered AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19.


Subject(s)
COVID-19 , Adult , Asymptomatic Infections , Cohort Studies , Female , Humans , Male , Pandemics , SARS-CoV-2
2.
Prev Med ; 153: 106860, 2021 12.
Article in English | MEDLINE | ID: covidwho-1525994

ABSTRACT

Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P < 0.001), with >80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last <2 days. Appreciable post-vaccine symptoms are associated with female sex, prior COVID-19, younger age, and hypertension. This information can aid clinicians in advising patients on the safety and expected symptomatology associated with vaccination.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19 Vaccines , Female , Humans , RNA, Messenger , Vaccination
3.
Non-conventional in English | [Unspecified Source], Grey literature | ID: grc-750502

ABSTRACT

Development of antibody protection during SARS-CoV-2 (CoV-2) infection is a pressing question for public health and for vaccine development. We developed highly sensitive CoV-2-specific antibody and neutralization assays. CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n=87) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. CoV-2 neutralization was determined in COVID-19 and convalescent plasma up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which was also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Further, subjects who donated plasma further out from the diagnosis of COVID-19 appeared to have lower titers. Interestingly, some COVID-19 patients also contained NAbs against SARS Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.

4.
J Clin Invest ; 131(20)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1470549

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.


Subject(s)
Autoimmunity , COVID-19/complications , Systemic Inflammatory Response Syndrome/immunology , Adaptive Immunity , Adolescent , Biomarkers/metabolism , COVID-19/genetics , COVID-19/immunology , COVID-19/metabolism , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Cytokine Release Syndrome/immunology , Female , Humans , Infant , Inflammation/immunology , Male , Mucocutaneous Lymph Node Syndrome/genetics , Mucocutaneous Lymph Node Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/metabolism , Neutrophil Activation , Proteomics , RNA-Seq , Receptors, Antigen, B-Cell/genetics , Severity of Illness Index , Systemic Inflammatory Response Syndrome/genetics , Systemic Inflammatory Response Syndrome/metabolism
5.
Mol Syst Biol ; 17(8): e10239, 2021 08.
Article in English | MEDLINE | ID: covidwho-1335457

ABSTRACT

Understanding the mechanism of SARS-CoV-2 infection and identifying potential therapeutics are global imperatives. Using a quantitative systems pharmacology approach, we identified a set of repurposable and investigational drugs as potential therapeutics against COVID-19. These were deduced from the gene expression signature of SARS-CoV-2-infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral-host interactome. We also identified immuno-modulating compounds aiming at suppressing hyperinflammatory responses in severe COVID-19 patients, based on the transcriptome of ACE2-overexpressing A549 cells. Experiments with Vero-E6 cells infected by SARS-CoV-2, as well as independent syncytia formation assays for probing ACE2/SARS-CoV-2 spike protein-mediated cell fusion using HEK293T and Calu-3 cells, showed that several predicted compounds had inhibitory activities. Among them, salmeterol, rottlerin, and mTOR inhibitors exhibited antiviral activities in Vero-E6 cells; imipramine, linsitinib, hexylresorcinol, ezetimibe, and brompheniramine impaired viral entry. These novel findings provide new paths for broadening the repertoire of compounds pursued as therapeutics against COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Evaluation, Preclinical/methods , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/genetics , COVID-19/virology , Chlorocebus aethiops , Drug Repositioning , HEK293 Cells , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/physiology , Humans , Imidazoles/pharmacology , Pyrazines/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Salmeterol Xinafoate/pharmacology , Vero Cells
6.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1311202

ABSTRACT

BACKGROUNDWeeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODSHere, we analyzed biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient's clinical response.RESULTSWe showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSIONThese mechanistic data on MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.


Subject(s)
COVID-19/etiology , COVID-19/physiopathology , Haptoglobins/physiology , Intestinal Mucosa/physiopathology , Protein Precursors/physiology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/etiology , Systemic Inflammatory Response Syndrome/physiopathology , Adolescent , Antigens, Viral/blood , Biomarkers/blood , COVID-19/virology , Case-Control Studies , Child , Child, Preschool , Female , Haptoglobins/antagonists & inhibitors , Humans , Infant , Infant, Newborn , Intestinal Mucosa/drug effects , Intestinal Mucosa/virology , Male , Oligopeptides/pharmacology , Permeability/drug effects , Proof of Concept Study , Protein Precursors/antagonists & inhibitors , Protein Precursors/blood , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/blood , Spike Glycoprotein, Coronavirus/immunology , Systemic Inflammatory Response Syndrome/virology , Young Adult
7.
Immunity ; 54(7): 1463-1477.e11, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1263294

ABSTRACT

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.


Subject(s)
Adenosine Triphosphate/metabolism , DNA, Mitochondrial/biosynthesis , Inflammasomes/drug effects , Metformin/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia/prevention & control , Animals , COVID-19/metabolism , COVID-19/prevention & control , Cytokines/genetics , Cytokines/metabolism , DNA, Mitochondrial/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Metformin/therapeutic use , Mice , Nucleoside-Phosphate Kinase/metabolism , Pneumonia/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/pathogenicity
8.
Structure ; 29(9): 951-962.e3, 2021 09 02.
Article in English | MEDLINE | ID: covidwho-1209570

ABSTRACT

We recently discovered a superantigen-like motif sequentially and structurally similar to a staphylococcal enterotoxin B (SEB) segment, near the S1/S2 cleavage site of the SARS-CoV-2 spike protein, which might explain the multisystem inflammatory syndrome (MIS-C) observed in children and the cytokine storm in severe COVID-19 patients. We show here that an anti-SEB monoclonal antibody (mAb), 6D3, can bind this viral motif at its polybasic (PRRA) insert to inhibit infection in live virus assays. The overlap between the superantigenic site of the spike and its proteolytic cleavage site suggests that the mAb prevents viral entry by interfering with the proteolytic activity of cell proteases (furin and TMPRSS2). The high affinity of 6D3 for this site originates from a polyacidic segment at its heavy chain CDR2. The study points to the potential utility of 6D3 for possibly treating COVID-19, MIS-C, or common colds caused by human coronaviruses that also possess a furin-like cleavage site.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal , Enterotoxins , Humans , Spike Glycoprotein, Coronavirus , Superantigens , Systemic Inflammatory Response Syndrome
9.
J Clin Invest ; 131(2)2021 01 19.
Article in English | MEDLINE | ID: covidwho-1172785

ABSTRACT

BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 1 million deaths worldwide; thus, there is an urgent need to develop preventive and therapeutic strategies. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) demonstrates nonspecific, protective innate immune-boosting effects. Here, we determined whether a history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a longitudinal, retrospective observational study of a diverse cohort of health care workers (HCWs).METHODSWe assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, which included information on BCG vaccination status and preexisting demographic and clinical characteristics, from an observational cohort of HCWs in a multisite Los Angeles health care organization. We used multivariate analysis to determine whether a history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion.RESULTSOf the 6201 HCWs, 29.6% reported a history of BCG vaccination, whereas 68.9% had not received BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as the incidence of self-reported clinical symptoms associated with coronavirus disease 2019 (COVID-19) were markedly decreased among HCWs with a history of BCG vaccination compared with those without BCG vaccination. After adjusting for age and sex, we found that a history of BCG vaccination, but not meningococcal, pneumococcal, or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion.CONCLUSIONSA history of BCG vaccination was associated with a decrease in the seroprevalence of anti-SARS-CoV-2 IgG and a lower number of participants who self-reported experiencing COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized, prospective clinical trials of BCG vaccination are urgently needed to confirm whether BCG vaccination can confer a protective effect against SARS-CoV-2 infection.


Subject(s)
BCG Vaccine/immunology , COVID-19/epidemiology , COVID-19/immunology , Health Personnel , Adult , BCG Vaccine/pharmacology , COVID-19/prevention & control , Cohort Studies , Female , Humans , Immunity, Innate , Influenza Vaccines/immunology , Influenza Vaccines/pharmacology , Longitudinal Studies , Los Angeles/epidemiology , Male , Meningococcal Vaccines/immunology , Meningococcal Vaccines/pharmacology , Middle Aged , Multivariate Analysis , Pneumococcal Vaccines/immunology , Pneumococcal Vaccines/pharmacology , Retrospective Studies , Seroepidemiologic Studies
10.
J Clin Invest ; 131(10)2021 05 17.
Article in English | MEDLINE | ID: covidwho-1133410

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vß chains results in Vß skewing, whereby T cells with specific Vß chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCRß variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the Vß chain encoded by TRBV11-2 (Vß21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.


Subject(s)
COVID-19/immunology , Complementarity Determining Regions/immunology , Histocompatibility Antigens Class I/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , COVID-19/genetics , Child , Complementarity Determining Regions/genetics , Female , Histocompatibility Antigens Class I/genetics , Humans , Male , Receptors, Antigen, T-Cell, alpha-beta/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Systemic Inflammatory Response Syndrome/genetics
11.
J Clin Invest ; 131(2)2021 01 19.
Article in English | MEDLINE | ID: covidwho-1120157

ABSTRACT

BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 1 million deaths worldwide; thus, there is an urgent need to develop preventive and therapeutic strategies. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) demonstrates nonspecific, protective innate immune-boosting effects. Here, we determined whether a history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a longitudinal, retrospective observational study of a diverse cohort of health care workers (HCWs).METHODSWe assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, which included information on BCG vaccination status and preexisting demographic and clinical characteristics, from an observational cohort of HCWs in a multisite Los Angeles health care organization. We used multivariate analysis to determine whether a history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion.RESULTSOf the 6201 HCWs, 29.6% reported a history of BCG vaccination, whereas 68.9% had not received BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as the incidence of self-reported clinical symptoms associated with coronavirus disease 2019 (COVID-19) were markedly decreased among HCWs with a history of BCG vaccination compared with those without BCG vaccination. After adjusting for age and sex, we found that a history of BCG vaccination, but not meningococcal, pneumococcal, or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion.CONCLUSIONSA history of BCG vaccination was associated with a decrease in the seroprevalence of anti-SARS-CoV-2 IgG and a lower number of participants who self-reported experiencing COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized, prospective clinical trials of BCG vaccination are urgently needed to confirm whether BCG vaccination can confer a protective effect against SARS-CoV-2 infection.


Subject(s)
BCG Vaccine/immunology , COVID-19/epidemiology , COVID-19/immunology , Health Personnel , Adult , BCG Vaccine/pharmacology , COVID-19/prevention & control , Cohort Studies , Female , Humans , Immunity, Innate , Influenza Vaccines/immunology , Influenza Vaccines/pharmacology , Longitudinal Studies , Los Angeles/epidemiology , Male , Meningococcal Vaccines/immunology , Meningococcal Vaccines/pharmacology , Middle Aged , Multivariate Analysis , Pneumococcal Vaccines/immunology , Pneumococcal Vaccines/pharmacology , Retrospective Studies , Seroepidemiologic Studies
12.
BMJ Open ; 11(2): e043584, 2021 02 12.
Article in English | MEDLINE | ID: covidwho-1081430

ABSTRACT

OBJECTIVE: We sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers. DESIGN: Observational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires. SETTINGS: A multisite healthcare delivery system located in Los Angeles County. PARTICIPANTS: A diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions. MAIN OUTCOMES: Using Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection. RESULTS: We observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, p<0.001) in addition to fever (OR 2.02, p=0.002) and myalgias (OR 1.65, p=0.035). After adjusting for potential confounders, seroprevalence was also associated with Hispanic ethnicity (OR 1.98, p=0.001) and African-American race (OR 2.02, p=0.027) as well as contact with a COVID-19-diagnosed individual in the household (OR 5.73, p<0.001) or clinical work setting (OR 1.76, p=0.002). Importantly, African-American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal COVID-19 diagnosis status, suggesting the contribution of unmeasured structural or societal factors. CONCLUSION AND RELEVANCE: The demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19.


Subject(s)
Antibodies, Viral/blood , COVID-19/diagnosis , Health Personnel , Seroepidemiologic Studies , Adult , Bayes Theorem , COVID-19/immunology , COVID-19 Serological Testing , Cohort Studies , Cross-Sectional Studies , Female , Humans , Los Angeles/epidemiology , Male , Middle Aged , SARS-CoV-2/immunology
13.
Commun Biol ; 4(1): 129, 2021 01 29.
Article in English | MEDLINE | ID: covidwho-1054066

ABSTRACT

Development of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n = 115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.


Subject(s)
Antibodies, Neutralizing/chemistry , Antibodies, Viral/chemistry , COVID-19/diagnosis , Coronavirus Nucleocapsid Proteins/chemistry , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Adult , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , COVID-19/immunology , COVID-19/virology , Convalescence , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus Nucleocapsid Proteins/metabolism , Enzyme-Linked Immunosorbent Assay/methods , Epitopes/chemistry , Epitopes/immunology , Epitopes/metabolism , Female , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Immune Sera/chemistry , Immunity, Humoral , Lentivirus/genetics , Lentivirus/immunology , Male , Middle Aged , Neutralization Tests , Phosphoproteins/chemistry , Phosphoproteins/immunology , Phosphoproteins/metabolism , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/immunology , Receptors, Virus/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Survival Analysis
14.
J Clin Invest ; 131(2)2021 01 19.
Article in English | MEDLINE | ID: covidwho-1035195

ABSTRACT

BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 1 million deaths worldwide; thus, there is an urgent need to develop preventive and therapeutic strategies. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) demonstrates nonspecific, protective innate immune-boosting effects. Here, we determined whether a history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a longitudinal, retrospective observational study of a diverse cohort of health care workers (HCWs).METHODSWe assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, which included information on BCG vaccination status and preexisting demographic and clinical characteristics, from an observational cohort of HCWs in a multisite Los Angeles health care organization. We used multivariate analysis to determine whether a history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion.RESULTSOf the 6201 HCWs, 29.6% reported a history of BCG vaccination, whereas 68.9% had not received BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as the incidence of self-reported clinical symptoms associated with coronavirus disease 2019 (COVID-19) were markedly decreased among HCWs with a history of BCG vaccination compared with those without BCG vaccination. After adjusting for age and sex, we found that a history of BCG vaccination, but not meningococcal, pneumococcal, or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion.CONCLUSIONSA history of BCG vaccination was associated with a decrease in the seroprevalence of anti-SARS-CoV-2 IgG and a lower number of participants who self-reported experiencing COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized, prospective clinical trials of BCG vaccination are urgently needed to confirm whether BCG vaccination can confer a protective effect against SARS-CoV-2 infection.


Subject(s)
BCG Vaccine/immunology , COVID-19/epidemiology , COVID-19/immunology , Health Personnel , Adult , BCG Vaccine/pharmacology , COVID-19/prevention & control , Cohort Studies , Female , Humans , Immunity, Innate , Influenza Vaccines/immunology , Influenza Vaccines/pharmacology , Longitudinal Studies , Los Angeles/epidemiology , Male , Meningococcal Vaccines/immunology , Meningococcal Vaccines/pharmacology , Middle Aged , Multivariate Analysis , Pneumococcal Vaccines/immunology , Pneumococcal Vaccines/pharmacology , Retrospective Studies , Seroepidemiologic Studies
15.
bioRxiv ; 2020 Nov 24.
Article in English | MEDLINE | ID: covidwho-955717

ABSTRACT

We recently discovered a superantigen-like motif, similar to Staphylococcal enterotoxin B (SEB), near the S1/S2 cleavage site of SARS-CoV-2 Spike protein, which might explain the multisystem-inflammatory syndrome (MIS-C) observed in children and cytokine storm in severe COVID-19 patients. We show here that an anti-SEB monoclonal antibody (mAb), 6D3, can bind this viral motif, and in particular its PRRA insert, to inhibit infection by blocking the access of host cell proteases, TMPRSS2 or furin, to the cleavage site. The high affinity of 6D3 for the furin-cleavage site originates from a poly-acidic segment at its heavy chain CDR2, a feature shared with SARS-CoV-2-neutralizing mAb 4A8. The affinity of 6D3 and 4A8 for this site points to their potential utility as therapeutics for treating COVID-19, MIS-C, or common cold caused by human coronaviruses (HCoVs) that possess a furin-like cleavage site.

18.
Proc Natl Acad Sci U S A ; 117(41): 25254-25262, 2020 10 13.
Article in English | MEDLINE | ID: covidwho-809109

ABSTRACT

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in children with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These children and adult patients with severe hyperinflammation present with a constellation of symptoms that strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to T cell receptors (TCRs) and/or major histocompatibility complex class II (MHCII) molecules. Here, using structure-based computational models, we demonstrate that the SARS-CoV-2 spike (S) glycoprotein exhibits a high-affinity motif for binding TCRs, and may form a ternary complex with MHCII. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in other SARS-related coronaviruses), which is highly similar in both sequence and structure to the bacterial superantigen staphylococcal enterotoxin B. This interaction between the virus and human T cells could be strengthened by a rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from an intercellular adhesion molecule (ICAM)-like motif shared between the SARS viruses from the 2003 and 2019 pandemics. A neurotoxin-like sequence motif on the receptor-binding domain also exhibits a high tendency to bind TCRs. Analysis of the TCR repertoire in adult COVID-19 patients demonstrates that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen activation. These data suggest that SARS-CoV-2 S may act as a superantigen to trigger the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Receptors, Antigen, T-Cell/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Superantigens/metabolism , Systemic Inflammatory Response Syndrome/immunology , Amino Acid Motifs , Betacoronavirus/chemistry , Betacoronavirus/genetics , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Enterotoxins/chemistry , Epitopes, T-Lymphocyte , Humans , Intercellular Adhesion Molecule-1/chemistry , Models, Molecular , Mutation , Neurotoxins/chemistry , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Protein Binding , Receptors, Antigen, T-Cell/chemistry , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Superantigens/chemistry , Superantigens/genetics , Systemic Inflammatory Response Syndrome/genetics , Systemic Inflammatory Response Syndrome/pathology
19.
medRxiv ; 2020 Oct 14.
Article in English | MEDLINE | ID: covidwho-663423

ABSTRACT

Development of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n=115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.

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