Multiple effects of TNFα inhibitors on the development of the adaptive immune response after SARS-CoV-2 vaccination (preprint)

Objectives The humoral immune response to SARS-CoV-2 vaccination in patients with chronic inflammatory disease (CID) declines more rapidly with TNFα inhibition. Furthermore, the efficacy of current vaccines against Omicron variants of concern (VOC) including BA.2 is limited. Alterations within immune cell populations, changes in IgG affinity and the ability to neutralise a pre-VOC strain and the BA.2 virus were investigated in these at-risk patients. Methods Serum levels of anti-SARS-CoV-2 IgG, IgG avidity and neutralising antibodies (NA) were determined in anti-TNFα patients (n=10) and controls (n=24 healthy individuals; n=12 patients under other disease-modifying anti-rheumatic drugs, oDMARD) before and after the second and third vaccination by ELISA, immunoblot and live virus neutralisation assay. SARS-CoV-2-specific B-and T cell subsets were analysed by multicolour flow cytometry. Results IgG avidity and anti-pre-VOC NA titres decreased faster in anti-TNFα recipients than in controls 6 months after the second vaccination (healthy individuals: avidity: p≤0.0001; NA: p=0.0347; oDMARDs: avidity: p=0.0012; NA: p=0.0293). Total plasma cell counts were increased in anti-TNFα patients (Healthy individuals: p=0.0344; oDMARDs: p=0.0254), whereas absolute numbers of SARS-CoV-2-specific cells were comparable 7 days after vaccination. These patients had lower BA.2 NA titres compared to both other groups, even after the third vaccination. Conclusions We show a reduced SARS-CoV-2 neutralising capacity in patients under TNFα blockade. In this cohort, the plasma cell response appears to be less specific and show stronger bystander activation. While these effects were observable after the first two vaccinations and with older VOC, the differences in responses to BA.2 were magnified. What is already known on this topic Patients with chronic inflammatory diseases treated with TNFα inhibitors show a greater decrease in SARS-CoV-2 IgG 6 months after the second vaccination than patients taking oDMARDs and healthy individuals. What this study adds Antibodies from patients taking TNFα blockers have a lower SARS-CoV-2 neutralising capacity and maturity. Plasma cells from these patients exhibit less specific immune reaction. SARS-CoV-2-specific T cells are less activated. Neutralisation against BA.2 is drastically reduced even after the third vaccination. How this study might affect research, practice or policy This study emphasizes the need to protect vulnerable groups such as patients using TNF inhibitors. They could benefit from Omicron-adapted vaccination, but most likely they need to be protected by additional means other than vaccination.

Interactive video retrieval evaluation at a distance: comparing sixteen interactive video search systems in a remote setting at the 10th Video Browser Showdown

The Video Browser Showdown addresses difficult video search challenges through an annual interactive evaluation campaign attracting research teams focusing on interactive video retrieval. The campaign aims to provide insights into the performance of participating interactive video retrieval systems, tested by selected search tasks on large video collections. For the first time in its ten year history, the Video Browser Showdown 2021 was organized in a fully remote setting and hosted a record number of sixteen scoring systems. In this paper, we describe the competition setting, tasks and results and give an overview of state-of-the-art methods used by the competing systems. By looking at query result logs provided by ten systems, we analyze differences in retrieval model performances and browsing times before a correct submission. Through advances in data gathering methodology and tools, we provide a comprehensive analysis of ad-hoc video search tasks, discuss results, task design and methodological challenges. We highlight that almost all top performing systems utilize some sort of joint embedding for text-image retrieval and enable specification of temporal context in queries for known-item search. Whereas a combination of these techniques drive the currently top performing systems, we identify several future challenges for interactive video search engines and the Video Browser Showdown competition itself.

The relationship between autoantibodies targeting GPCRs and the renin-angiotensin system associates with COVID-19 severity (preprint)

The coronavirus disease 2019 (COVID-19) can evolve to clinical manifestations resembling systemic autoimmune diseases, with the presence of autoantibodies that are still poorly characterized. To address this issue, we performed a cross-sectional study of 246 individuals to determine whether autoantibodies targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS)-related molecules were associated with COVID-19-related clinical outcomes. Moderate and severe patients exhibited the highest autoantibody levels, relative to both healthy controls and patients with mild COVID-19 symptoms. Random Forest, a machine learning model, ranked anti-GPCR autoantibodies targeting downstream molecules in the RAS signaling pathway such as the angiotensin II type 1 and Mas receptor, and the chemokine receptor CXCR3 as the three strongest predictors of severe disease. Moreover, while the autoantibody network signatures were relatively conserved in patients with mild COVID-19 compared to healthy controls, they were disrupted in moderate and most perturbed in severe patients. Our data indicate that the relationship between autoantibodies targeting GPCRs and RAS-related molecules associates with the clinical severity of COVID-19, suggesting novel molecular pathways for therapeutic interventions.

New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations (preprint)

Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.

Longitudinal multi-omics analysis identifies responses of megakaryocytes, erythroid cells and plasmablasts as hallmarks of severe COVID-19 trajectories (preprint)

The pandemic spread of the potentially life-threatening disease COVID-19 requires a thorough understanding of the longitudinal dynamics of host responses. Temporal resolution of cellular features associated with a severe disease trajectory will be a pre-requisite for finding disease outcome predictors. Here, we performed a longitudinal multi-omics study using a two-centre German cohort of 13 patients (from Cologne and Kiel, cohort 1). We analysed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. The results from single-cell and bulk transcriptome analyses were validated in two independent cohorts of COVID-19 patients from Bonn (18 patients, cohort 2) and Nijmegen (40 patients, cohort 3), respectively. We observed an increase of proliferating, activated plasmablasts in severe COVID-19, and show a distinct expression pattern related to a hyperactive cellular metabolism of these cells. We further identified a notable expansion of type I IFN-activated circulating megakaryocytes and their progenitors, indicative of emergency megakaryopoiesis, which was confirmed in cohort 2. These changes were accompanied by increased erythropoiesis in the critical phase of the disease with features of hypoxic signalling. Finally, projecting megakaryocyte- and erythroid cell-derived co-expression modules to longitudinal blood transcriptome samples from cohort 3 confirmed an association of early temporal changes of these features with fatal COVID-19 disease outcome. In sum, our longitudinal multi-omics study demonstrates distinct cellular and gene expression dynamics upon SARS-CoV-2 infection, which point to metabolic shifts of circulating immune cells, and reveals changes in megakaryocytes and increased erythropoiesis as important outcome indicators in severe COVID-19 patients.

Pre-existing T cell memory as a risk factor for severe 1 COVID-19 in the elderly (preprint)

Coronavirus disease 2019 (COVID-19) displays high clinical variability but the parameters that determine disease severity are still unclear. Pre-existing T cell memory has been hypothesized as a protective mechanism but conclusive evidence is lacking. Here we demonstrate that all unexposed individuals harbor SARS-CoV-2-specific memory T cells with marginal cross-reactivity to common cold corona and other unrelated viruses. They display low functional avidity and broad protein target specificities and their frequencies correlate with the overall size of the CD4+ memory compartment reflecting the immunological age of an individual. COVID-19 patients have strongly increased SARS-CoV-2-specific inflammatory T cell responses that are correlated with severity. Strikingly however, patients with severe COVID-19 displayed lower TCR functional avidity and less clonal expansion. Our data suggest that a low avidity pre-existing T cell memory negatively impacts on the T cell response quality against neoantigens such as SARS-CoV-2, which may predispose to develop inappropriate immune reactions especially in the elderly. We propose the immunological age as an independent risk factor to develop severe COVID-19.