Atypical B cells and impaired SARS-CoV-2 neutralization following heterologous vaccination in the elderly

Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here, we show that individuals 70 years or older (median age 73, range 70-75) who received a primary two-dose schedule with AZD1222 and booster third dose with mRNA vaccine achieve significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared with those younger than 70 (median age 66, range 54-69) at 1 month post booster. Impaired neutralization potency and breadth post third dose in the elderly is associated with circulating "atypical" spike-specific B cells expressing CD11c and FCRL5. However, when considering individuals who received three doses of mRNA vaccine, we did not observe differences in neutralization or enrichment in atypical B cells. This work highlights the finding that AdV and mRNA COVID-19 vaccine formats differentially instruct the memory B cell response

The Human Cell Atlas.

The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community

The Human Cell Atlas White Paper

The Human Cell Atlas (HCA) will be made up of comprehensive reference maps of all human cells - the fundamental units of life - as a basis for understanding fundamental human biological processes and diagnosing, monitoring, and treating disease. It will help scientists understand how genetic variants impact disease risk, define drug toxicities, discover better therapies, and advance regenerative medicine. A resource of such ambition and scale should be built in stages, increasing in size, breadth, and resolution as technologies develop and understanding deepens. We will therefore pursue Phase 1 as a suite of flagship projects in key tissues, systems, and organs. We will bring together experts in biology, medicine, genomics, technology development and computation (including data analysis, software engineering, and visualization). We will also need standardized experimental and computational methods that will allow us to compare diverse cell and tissue types - and samples across human communities - in consistent ways, ensuring that the resulting resource is truly global. This document, the first version of the HCA White Paper, was written by experts in the field with feedback and suggestions from the HCA community, gathered during recent international meetings. The White Paper, released at the close of this yearlong planning process, will be a living document that evolves as the HCA community provides additional feedback, as technological and computational advances are made, and as lessons are learned during the construction of the atlas

Clinical outreach refresher trainings in crisis settings (S-CORT): clinical management of sexual violence survivors and manual vacuum aspiration in Burkina Faso, Nepal, and South Sudan

© 2017 The Inter-agency Working Group on Reproductive Health in Crises. Published by Informa UK Limited, trading as Taylor & Francis Group. During the early humanitarian response to a crisis, there is limited time to train health providers in the life-saving clinical services of the Minimum Initial Services Package (MISP) for Reproductive Health. The Training Partnership Initiative of the Inter-agency Working Group on Reproductive Health in Crises developed the S-CORT model (Sexual and reproductive health Clinical Outreach Refresher Training) for service providers operating in acute humanitarian settings and needing to rapidly refresh their knowledge and skills. Through qualitative research, this study aimed to determine the operational enablers and barriers related to the implementation of two S-CORT modules: clinical management of sexual violence survivors (CMoSVS) and manual vacuum aspiration (MVA). Across three participating countries (Burkina Faso, Nepal, and South Sudan), 135 health staff attended the CMoSVS refresher training and 94 the MVA refresher training. Results from the focus group discussions and in-depth interviews suggest that the S-CORT approach is respectful of human rights and quality of care principles. Furthermore, it is potentially effective in enhancing the knowledge and skills of existing trained service providers, strengthening their capacity, and changing their attitudes towards abortion-related services, for example. The S-CORT is a promising model for implementation in the acute phase of an emergency upon stabilisation of the security situation. The model can also be integrated into broader post-crisis capacity development efforts. Future operational research should emphasise not only an assessment of new modules’ contents, but whether implementing this refresher training model in remote outreach settings is feasible, effective, and efficient

Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells

Multiple psychiatric disorders have been associated with abnormalities in both the innate and adaptive immune systems. The role of these abnormalities in pathogenesis, and whether they are driven by psychiatric risk variants, remains unclear. We test for enrichment of GWAS variants associated with multiple psychiatric disorders (cross-disorder or trans-diagnostic risk), or 5 specific disorders (cis-diagnostic risk), in regulatory elements in immune cells. We use three independent epigenetic datasets representing multiple organ systems and immune cell subsets. Trans-diagnostic and cis-diagnostic risk variants (for schizophrenia and depression) are enriched at epigenetically active sites in brain tissues and in lymphoid cells, especially stimulated CD4+ T cells. There is no evidence for enrichment of either trans-risk or cis-risk variants for schizophrenia or depression in myeloid cells. This suggests a possible model where environmental stimuli activate T cells to unmask the effects of psychiatric risk variants, contributing to the pathogenesis of mental health disorders.This work was funded by an Medical Research Council award MR/S006257/1 (M.E.L.); NIHR Senior Investigator award (E.T.B); Open Targets grant OTAR040 (B.S., G.T.). Wellcome Trust grant WT206194 (G.T.); US Veterans Affairs Career Development Award (D.F.L.); NIHR Research Professorship RP-2017-08-ST2-002 (M.R.C.). This work was additionally supported by the NIHR Cambridge Biomedical Research Centre

Research data supporting 'Peripheral blood cell immunophenotyping reveals distinct subgroups of inflamed depression', Biological Psychiatry, 2019

Clinical and cell count data from NIMA Consortium (PI: Ed Bullmore) to support publication 'Peripheral blood cell immunophenotyping reveals distinct subgroups of inflamed depression', Biological Psychiatry, 2019. Authors: ME Lynall, L Turner, J Bhatti, J Cavanagh, P de Boer, V Mondelli, D Jones, WC Drevets, P Cowan, C Pariante, L Pointon, NIMA Consortium, M Clatworthy, E Bullmore $$\$$ [R] code to support the analyses and figure generation is available on Github (maryellenlynall/2019_depression_flow_cytometry). $$\$$ BACKGROUND: Depression has been associated with increased inflammatory proteins but changes in circulating immune cells are less well defined. $$\$$ METHODS: We used multi-parametric flow cytometry to count 14 subsets of peripheral blood cells in 206 cases of depression and 77 age- and sex-matched controls (total N = 283). We used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity. $$\$$ RESULTS: Depressed cases, compared to controls, had significantly increased immune cell counts, especially neutrophils, CD4+ T cells and monocytes, and increased inflammatory proteins (C-reactive protein, CRP, and interleukin-6, IL-6). Within-group analysis of cases demonstrated significant associations between the severity of depressive symptoms and increased myeloid and CD4+ T cell counts. Depressed cases were partitioned into two subgroups by forced binary clustering of cell counts: the inflamed depression subgroup (N=81 out of 206; 39%) had increased monocyte, CD4+ and neutrophil counts, increased CRP and IL-6, and was more depressed than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified four subgroups of depressed cases: two of which (N=38 and N=100; 67% collectively) were associated with increased inflammatory proteins and more severe depression, but differed in terms of myeloid and lymphoid cell counts. Results were robust to potentially confounding effects of age, sex, body mass index, recent infection, and tobacco use. $$\$$ CONCLUSIONS: Peripheral immune cell counts were used to distinguish inflamed and uninflamed subgroups of depression and to indicate that there may be mechanistically distinct subgroups of inflamed depression.Wellcome Trust, Medical Research Council, Addenbrooke's Charitable Trust, NIHR (see paper for further details