Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.

BACKGROUNDVaccine-elicited adaptive immunity is a prerequisite for control of SARS-CoV-2 infection. Multiple sclerosis (MS) disease-modifying therapies (DMTs) differentially target humoral and cellular immunity. A comprehensive comparison of the effects of MS DMTs on SARS-CoV-2 vaccine-specific immunity is needed, including quantitative and functional B and T cell responses.METHODSSpike-specific Ab and T cell responses were measured before and following SARS-CoV-2 vaccination in a cohort of 80 study participants, including healthy controls and patients with MS in 6 DMT groups: untreated and treated with glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NTZ), sphingosine-1-phosphate (S1P) receptor modulators, and anti-CD20 mAbs. Anti-spike-Ab responses were assessed by Luminex assay, VirScan, and pseudovirus neutralization. Spike-specific CD4+ and CD8+ T cell responses were characterized by activation-induced marker and cytokine expression and tetramer.RESULTSAnti-spike IgG levels were similar between healthy control participants and patients with untreated MS and those receiving GA, DMF, or NTZ but were reduced in anti-CD20 mAb- and S1P-treated patients. Anti-spike seropositivity in anti-CD20 mAb-treated patients was correlated with CD19+ B cell levels and inversely correlated with cumulative treatment duration. Spike epitope reactivity and pseudovirus neutralization were reduced in anti-CD20 mAb- and S1P-treated patients. Spike-specific CD4+ and CD8+ T cell reactivity remained robust across all groups, except in S1P-treated patients, in whom postvaccine CD4+ T cell responses were attenuated.CONCLUSIONThese findings from a large cohort of patients with MS exposed to a wide spectrum of MS immunotherapies have important implications for treatment-specific COVID-19 clinical guidelines.FUNDINGNIH grants 1K08NS107619, K08NS096117, R01AI159260, R01NS092835, R01AI131624, and R21NS108159; NMSS grants TA-1903-33713 and RG1701-26628; Westridge Foundation; Chan Zuckerberg Biohub; Maisin Foundation.

Anti-SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms.

Importance: Neuropsychiatric manifestations of COVID-19 have been reported in the pediatric population. Objective: To determine whether anti-SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction. Design, Setting, and Participants: This case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase-polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children's Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction or rapid antigen test. Main Outcomes and Measures: Detection and characterization of CSF anti-SARS-CoV-2 IgG and antineural antibodies. Results: Of 3 included teenaged patients, 2 patients had intrathecal anti-SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomic immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) in 1 patient who appeared to have a robust response to immunotherapy were also validated. Conclusions and Relevance: Pediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti-SARS-CoV-2 and antineural antibodies in their CSF and may respond to immunotherapy.

Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms.

Individuals with coronavirus disease 2019 (COVID-19) frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single-cell RNA sequencing (scRNA-seq) and cytokine analyses of cerebrospinal fluid (CSF) and blood from individuals with COVID-19 with neurological symptoms, we find compartmentalized, CNS-specific T cell activation and B cell responses. All affected individuals had CSF anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are present only during brain infection and not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from an individual with COVID-19 and found that these monoclonal antibodies (mAbs) target antiviral and antineural antigens, including one mAb that reacted to spike protein and neural tissue. CSF immunoglobulin G (IgG) from 5 of 7 patients showed antineural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of individuals with COVID-19 and suggests a role of autoimmunity in neurologic sequelae of COVID-19.

ReScan, a Multiplex Diagnostic Pipeline, Pans Human Sera for SARS-CoV-2 Antigens.

Comprehensive understanding of the serological response to SARS-CoV-2 infection is important for both pathophysiologic insight and diagnostic development. Here, we generate a pan-human coronavirus programmable phage display assay to perform proteome-wide profiling of coronavirus antigens enriched by 98 COVID-19 patient sera. Next, we use ReScan, a method to efficiently sequester phage expressing the most immunogenic peptides and print them onto paper-based microarrays using acoustic liquid handling, which isolates and identifies nine candidate antigens, eight of which are derived from the two proteins used for SARS-CoV-2 serologic assays: spike and nucleocapsid proteins. After deployment in a high-throughput assay amenable to clinical lab settings, these antigens show improved specificity over a whole protein panel. This proof-of-concept study demonstrates that ReScan will have broad applicability for other emerging infectious diseases or autoimmune diseases that lack a valid biomarker, enabling a seamless pipeline from antigen discovery to diagnostic using one recombinant protein source.