The SARS-CoV-2 antibody neutralization response and its evasion by emerging viral variants are unknown. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus-cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 RT-PCR-confirmed COVID-19 individuals with detailed demographics and followed up to seven months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization were associated with COVID-19 severity. A subgroup of ‘high responders’ maintained high neutralizing responses over time, representing ideal convalescent plasma therapy donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal plasma donors and vaccine monitoring and design.One Sentence SummaryNeutralizing antibody responses to SARS-CoV-2 are sustained, associated with COVID19 severity, and evaded by emerging viral variants

Patients with indolent lymphoma undertaking recurrent or continuous B cell suppression are at risk of severe COVID‐19. Patients and healthy controls (HC; N = 13) received two doses of BNT162b2: follicular lymphoma (FL; N = 35) who were treatment naïve (TN; N = 11) or received immunochemotherapy (ICT; N = 23) and Waldenström's macroglobulinemia (WM; N = 37) including TN ( N = 9), ICT ( N = 14), or treated with Bruton's tyrosine kinase inhibitors (BTKi; N = 12). Anti‐spike immunoglobulin G (IgG) was determined by a high‐sensitivity flow‐cytometric assay, in addition to live‐virus neutralization. Antigen‐specific T cells were identified by coexpression of CD69/CD137 and CD25/CD134 on T cells. A subgroup ( N = 29) were assessed for third mRNA vaccine response, including omicron neutralization. One month after second BNT162b2, median anti‐spike IgG mean fluorescence intensity (MFI) in FL ICT patients (9977) was 25‐fold lower than TN (245 898) and HC (228 255, p = .0002 for both). Anti‐spike IgG correlated with lymphocyte count ( r = .63; p = .002), and time from treatment ( r = .56; p = .007), on univariate analysis, but only with lymphocyte count on multivariate analysis ( p = .03). In the WM cohort, median anti‐spike IgG MFI in BTKi patients (39 039) was reduced compared to TN (220 645, p = .0008) and HC ( p < .0001). Anti‐spike IgG correlated with neutralization of the delta variant ( r = .62, p < .0001). Median neutralization titer for WM BTKi (0) was lower than HC (40, p < .0001) for early‐clade and delta. All cohorts had functional T cell responses. Median anti‐spike IgG decreased 4‐fold from second to third dose ( p = .004). Only 5 of 29 poor initial responders assessed after third vaccination demonstrated seroconversion and improvement in neutralization activity, including to the omicron variant.

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Background and ObjectivesMultiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by infiltration of immune cells in multifocal areas of the CNS. The specific molecular processes allowing autoreactive immune cells to enter the CNS compartment through the blood-brain barrier remain elusive.MethodsUsing endothelial cell (EC) enrichment and single-cell RNA sequencing, we characterized the cells implicated in the neuroinflammatory processes in experimental autoimmune encephalomyelitis, an animal model of MS. Validations on human MS brain sections of the most differentially expressed genes in venous ECs were performed using immunohistochemistry and confocal microscopy.ResultsWe found an upregulation of genes associated with antigen presentation and interferon in most populations of CNS-resident cells, including ECs. Interestingly, instead of transcriptionally distinct profiles, a continuous gradient of gene expression separated the arteriovenous zonation of the brain vasculature. However, differential gene expression analysis presented more transcriptomic alterations on the venous side of the axis, suggesting a prominent role of venous ECs in neuroinflammation. Furthermore, analysis of ligand-receptor interactions identified important potential molecular communications between venous ECs and infiltrated immune populations. To confirm the relevance of our observation in the context of human disease, we validated the protein expression of the most upregulated genes (Ackr1andLcn2) in MS lesions.DiscussionIn this study, we provide a landscape of the cellular heterogeneity associated with neuroinflammation. We also present important molecular insights for further exploration of specific cell processes that promote infiltration of immune cells inside the brain of experimental autoimmune encephalomyelitis mice.