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1.
Viruses ; 14(5):882, 2022.
Article in English | MDPI | ID: covidwho-1810323

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has now been continuing for more than two years. The infection causes COVID-19, a disease of the respiratory and cardiovascular system of variable severity. Here, the humoral immune response of 80 COVID-19 patients from the University Hospital Frankfurt/Main, Germany, was characterized longitudinally. The SARS-CoV-2 neutralization activity of serum waned over time. The neutralizing potential of serum directed towards the human alpha-coronavirus NL-63 (NL63) also waned, indicating that no cross-priming against alpha-coronaviruses occurred. A subset of the recovered patients (n = 13) was additionally vaccinated with the mRNA vaccine Comirnaty. Vaccination increased neutralization activity against SARS-CoV-2 wild-type (WT), Delta, and Omicron, although Omicron-specific neutralization was not detectable prior to vaccination. In addition, the vaccination induced neutralizing antibodies against the more distantly related SARS-CoV-1 but not against NL63. The results indicate that although SARS-CoV-2 humoral immune responses induced by infection wane, vaccination induces a broad neutralizing activity against multiple SARS-CoVs, but not to the common cold alpha-coronavirus NL63.

3.
Dtsch Arztebl Int ; (Forthcoming)2022 Feb 25.
Article in English | MEDLINE | ID: covidwho-1662560

ABSTRACT

BACKGROUND: Contact with a pathogen is followed by variable courses of infectious disease, which are only partly explicable by classical risk factors. The susceptibility to infection is variable, as is the course of disease after infection. In this review, we discuss the extent to which this variation is due to genetic factors of the affected individual (the host). METHODS: Selective review of the literature on host genetics in infectious disease, with special attention to the pathogens SARS-CoV-2, influenza viruses, Mycobacterium tuberculosis, and human immunodeficiency virus (HIV). RESULTS: Genetic variants of the host contribute to the pathogenesis of infectious diseases. For example, in HIV infection, a relatively common variant leading to a loss of function of the HIV co-receptor CCR5 affects the course of the disease, as do variants in genes of the major histocompatibility complex (MHC) region. Rare monogenic variants of the interferon immune response system contribute to severe disease courses in COVID-19 and influenza (type I interferon in these two cases) and in tuberculosis (type II interferon). An estimated 1.8% of lifethreatening courses of COVID-19 in men under age 60 are caused by a deficiency of toll-like receptor 7. The scientific understanding of host genetic factors has already been beneficial to the development of effective drugs. In a small number of cases, genetic information has also been used for individual therapeutic decision-making and for the identification of persons at elevated risk. CONCLUSION: A comprehensive understanding of host genetics can improve the care of patients with infectious diseases. Until the present, the clinical utility of host genetics has been limited to rare cases; in the future, polygenic risk scores summarizing the relevant genetic variants in each patient will enable a wider benefit. To make this possible, multicenter studies are needed that will systematically integrate clinical and genetic data.

4.
Artif Intell Life Sci ; 1: 100020, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1588542

ABSTRACT

Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center 'Lean European Open Survey on SARS-CoV-2-infected patients' (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimer's Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.

5.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-296314

ABSTRACT

The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections. We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R. We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.5-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab. In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which however, might be circumvented by a combination therapy with casirivimab together.

6.
Eur J Neurol ; 28(12): 3925-3937, 2021 12.
Article in English | MEDLINE | ID: covidwho-1515204

ABSTRACT

BACKGROUND AND PURPOSE: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry. METHODS: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression. RESULTS: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20-1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07-1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19. CONCLUSION: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection.


Subject(s)
COVID-19 , Neurodegenerative Diseases , Stroke , Headache , Humans , SARS-CoV-2
7.
Clin Infect Dis ; 2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1483417

ABSTRACT

BACKGROUND: At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with Coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict COVID-19 illness. However, the results are not conclusive, as critical illness can drastically alter a patient's microbiome through multiple confounders. METHODS: To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multi-center, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate and severe COVID-19 (n=322 participants). RESULTS: In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. CONCLUSION: In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.

8.
J Infect Dis ; 224(7): 1109-1114, 2021 10 13.
Article in English | MEDLINE | ID: covidwho-1470152

ABSTRACT

Whether monoclonal antibodies are able to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern has been investigated using pseudoviruses. In this study we show that bamlanivimab, casirivimab, and imdevimab efficiently neutralize authentic SARS-CoV-2, including variant B.1.1.7 (alpha), but variants B.1.351 (beta) and P.2 (zeta) were resistant against bamlanivimab and partially resistant to casirivimab. Whether antibodies are able to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variantshas been investigated using pseudoviruses. We show that authentic SARS-CoV-2 carrying E484K were resistant against bamlanivimab and less susceptible to casirivimab, convalescent and vaccine-elicited sera.


Subject(s)
COVID-19/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Amino Acid Substitution , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Humans , Mutation, Missense , Neutralization Tests
9.
Int J Mol Sci ; 22(19)2021 Sep 26.
Article in English | MEDLINE | ID: covidwho-1438630

ABSTRACT

A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0-3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-ß signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.


Subject(s)
COVID-19/complications , COVID-19/genetics , MicroRNAs/genetics , Respiratory Insufficiency/etiology , Respiratory Insufficiency/genetics , Aged , Aged, 80 and over , Blood Coagulation , COVID-19/blood , Disease Progression , Down-Regulation , Female , Humans , Inflammation/blood , Inflammation/etiology , Inflammation/genetics , Male , MicroRNAs/blood , Middle Aged , Respiratory Insufficiency/blood , SARS-CoV-2/isolation & purification , Severity of Illness Index
11.
Viruses ; 13(9)2021 08 26.
Article in English | MEDLINE | ID: covidwho-1374534

ABSTRACT

The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections. We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R. We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.51-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab. In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which, however, might be circumvented by combination therapy with casirivimab together.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Alleles , Amino Acid Substitution , Cell Line , Genotype , Host-Pathogen Interactions , Humans , Neutralization Tests
12.
Immunity ; 53(6): 1258-1271.e5, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-988080

ABSTRACT

CD4+ T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized SARS-CoV-2-reactive CD4+ T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4+ memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4+ T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4+ T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Receptors, Antigen, T-Cell/metabolism , Rhinovirus/immunology , SARS-CoV-2/immunology , Antigens, Viral/immunology , Cells, Cultured , Cross Reactions , Disease Progression , Environmental Exposure , Humans , Immunologic Memory , Lymphocyte Activation , Protein Binding , Severity of Illness Index , T-Cell Antigen Receptor Specificity
15.
Cell ; 182(4): 843-854.e12, 2020 08 20.
Article in English | MEDLINE | ID: covidwho-641071

ABSTRACT

The SARS-CoV-2 pandemic has unprecedented implications for public health, social life, and the world economy. Because approved drugs and vaccines are limited or not available, new options for COVID-19 treatment and prevention are in high demand. To identify SARS-CoV-2-neutralizing antibodies, we analyzed the antibody response of 12 COVID-19 patients from 8 to 69 days after diagnosis. By screening 4,313 SARS-CoV-2-reactive B cells, we isolated 255 antibodies from different time points as early as 8 days after diagnosis. Of these, 28 potently neutralized authentic SARS-CoV-2 with IC100 as low as 0.04 µg/mL, showing a broad spectrum of variable (V) genes and low levels of somatic mutations. Interestingly, potential precursor sequences were identified in naive B cell repertoires from 48 healthy individuals who were sampled before the COVID-19 pandemic. Our results demonstrate that SARS-CoV-2-neutralizing antibodies are readily generated from a diverse pool of precursors, fostering hope for rapid induction of a protective immune response upon vaccination.


Subject(s)
Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/isolation & purification , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/genetics , Antibodies, Viral/immunology , B-Lymphocytes/immunology , Betacoronavirus/immunology , COVID-19 , Humans , Immunoglobulin Variable Region/genetics , Immunoglobulin Variable Region/immunology , Immunologic Memory , Longitudinal Studies , Pandemics , SARS-CoV-2 , Somatic Hypermutation, Immunoglobulin
16.
Chirurg ; 91(7): 576-585, 2020 Jul.
Article in German | MEDLINE | ID: covidwho-615027

ABSTRACT

BACKGROUND: The SARS-CoV-2/COVID-19 pandemic necessitates a rapid reorganization of the hospital procedures. The establishment of centers dedicated to COVID-19 treatment and care also necessitates preparation of the surgical departments for the forthcoming emergency interventions for infected patients and patients with an unclear infection status. This article summarizes the evidence on standards for personal protective equipment for personnel in the central emergency admission department and in the operations area as well as restructuring measures for the procedures in the operations area in a COVID-plus area. METHOD: A systematic literature search was carried out. RESULTS: The grey area of unknown infected and potential transmitters of SARS-CoV-2/COVID-19 is high. Patients with an unclear infection status or who are highly suspected of having an infection should be classified as infectious until the contrary can be proven. The protection of personnel in healthcare professions against infections is of particular importance. The supply of adequate personal protective equipment in a risk-stratified form can substantially influence the success of combating the pandemic. Most operations must be assessed as aerosol-forming procedures and necessitate the maximum protection of personnel working directly on the patient. Particular attention should be paid to obligatory hygiene regulatory measures for protection against contamination during the reorganization in the operations area and on the transport routes between the wards. CONCLUSION: The correct personal protective equipment considering the occupational safety helps to sustainably protect personnel from infections. Reorganizational measures in the operating room are urgently indicated for potential aerosol-forming procedures in infected patients or patients with an unclear infection status. The current dynamic situation necessitates a high level of flexibility as well as reassessment and adaptation of the measures at short intervals.


Subject(s)
Coronavirus Infections , Pandemics , Personal Protective Equipment , Pneumonia, Viral , Primary Health Care , Betacoronavirus , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Humans , Infection Control , Infectious Disease Transmission, Patient-to-Professional , Pandemics/prevention & control , Patient Care/standards , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , SARS-CoV-2 , United States
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