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BackgroundAdequate response to the SARS-CoV-2 vaccine represents an important treatment goal in caring for patients with multiple sclerosis (MS) during the ongoing COVID-19 pandemic. Previous data so far have demonstrated lower spike-specific IgG responses following two SARS-CoV-2 vaccinations in MS patients treated with sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb) compared to other disease modifying therapies (DMTs). It is unknown whether subsequent vaccinations can augment antibody responses in these patients.ObjectivesThe goal of this observational study was to determine the effects of a third SARS-CoV-2 vaccination on antibody and T cell responses in MS patients treated with anti-CD20 mAb or S1P receptor modulators.MethodsVaccine responses in patients treated with anti-CD20 antibodies (ocrelizumab and ofatumumab) or S1P receptor modulators (fingolimod and siponimod) were evaluated before and after third SARS-CoV-2 vaccination as part of an ongoing longitudinal study. Total spike protein and spike receptor binding domain (RBD)-specific IgG responses were measured by Luminex bead-based assay. Spike-specific CD4+ and CD8+ T cell responses were measured by activation-induced marker expression.ResultsMS patients and healthy controls were enrolled before and following SARS-CoV-2 vaccination. A total of 31 MS patients (n = 10 ofatumumab, n = 13 ocrelizumab, n = 8 S1P) and 10 healthy controls were evaluated through three SARS-CoV-2 vaccinations. Compared to healthy controls, total spike IgG was significantly lower in anti-CD20 mAb-treated patients and spike RBD IgG was significantly lower in anti-CD20 mAb and S1P-treated patients following a third vaccination. While seropositivity was 100% in healthy controls after a third vaccination, total spike IgG and spike RBD IgG seropositivity were lower in ofatumumab (60% and 60%, respectively), ocrelizumab (85% and 46%, respectively), and S1P-treated patients (100% and 75%, respectively). Longer treatment duration, including prior treatment history, appeared to negatively impact antibody responses. Spike-specific CD4+ and CD8+ T cell responses were well maintained across all groups following a third vaccination. Finally, immune responses were also compared in patients who were vaccinated prior to or following ofatumumab treatment. Antibody responses were significantly higher in those patients who received their primary SARS-CoV-2 vaccination prior to initiating ofatumumab treatment.ConclusionsThis study adds to the evolving understanding of SARS-CoV-2 vaccine responses in people with MS treated with disease-modifying therapies (DMTs) known to suppress humoral immunity. Our findings provide important information for optimizing vaccine immunity in at-risk MS patient populations.

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.

[This corrects the article DOI: 10.3389/fneur.2021.728700.].

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.

The development of autoimmune antibody panels has improved the diagnosis of paraneoplastic neurological disorders (PNDs) of the brain and spinal cord. Here, we present a case of a woman with a history of breast cancer who presented with a subacute sensory ataxia that progressed over 18 months. Her examination and diagnostic studies were consistent with a myelopathy. Metabolic, infectious, and autoimmune testing were non-diagnostic. However, she responded to empirical immunosuppression, prompting further workup for an autoimmune etiology. An unbiased autoantibody screen utilizing phage display immunoprecipitation sequencing (PhIP-Seq) identified antibodies to the anti-Yo antigens cerebellar degeneration related protein 2 like (CDR2L) and CDR2, which were subsequently validated by immunoblot and cell-based overexpression assays. Furthermore, CDR2L protein expression was restricted to HER2 expressing tumor cells in the patient's breast tissue. Recent evidence suggests that CDR2L is likely the primary antigen in anti-Yo paraneoplastic cerebellar degeneration, but anti-Yo myelopathy is poorly characterized. By immunostaining, we detected neuronal CDR2L protein expression in the murine and human spinal cord. This case demonstrates the diagnostic utility of unbiased assays in patients with suspected PNDs, supports prior observations that anti-Yo PND can be associated with isolated myelopathy, and implicates CDR2L as a potential antigen in the spinal cord.

Vaccine-elicited adaptive immunity is an essential prerequisite for effective prevention and control of coronavirus 19 (COVID-19). Treatment of multiple sclerosis (MS) involves a diverse array of disease-modifying therapies (DMTs) that target antibody and cell-mediated immunity, yet a comprehensive understanding of how MS DMTs impact SARS-CoV-2 vaccine responses is lacking. We completed a detailed analysis of SARS-CoV-2 vaccine-elicited spike antigen-specific IgG and T cell responses in a cohort of healthy controls and MS participants in six different treatment categories. Two specific DMT types, sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb), resulted in significantly reduced spike-specific IgG responses. Longer duration of anti-CD20 mAb treatment prior to SARS-CoV-2 vaccination were associated with absent antibody responses. Except for reduced CD4+ T cell responses in S1P-treated patients, spike-specific CD4+ and CD8+ T cell reactivity remained robust across all MS treatment types. These findings have important implications for clinical practice guidelines and vaccination recommendations in MS patients and other immunosuppressed populations.

One third of COVID-19 patients develop significant neurological symptoms, yet SARS-CoV-2 is rarely detected in central nervous system (CNS) tissue, suggesting a potential role for parainfectious processes, including neuroimmune responses. We therefore examined immune parameters in cerebrospinal fluid (CSF) and blood samples from a cohort of patients with COVID-19 and significant neurological complications. We found divergent immunological responses in the CNS compartment, including increased levels of IL-12 and IL-12-associated innate and adaptive immune cell activation. Moreover, we found increased proportions of B cells in the CSF relative to the periphery and evidence of clonal expansion of CSF B cells, suggesting a divergent intrathecal humoral response to SARS-CoV-2. Indeed, all COVID-19 cases examined had anti-SARS-CoV-2 IgG antibodies in the CSF whose target epitopes diverged from serum antibodies. We directly examined whether CSF resident antibodies target self-antigens and found a significant burden of CNS autoimmunity, with the CSF from most patients recognizing neural self-antigens. Finally, we produced a panel of monoclonal antibodies from patients' CSF and show that these target both anti-viral and anti-neural antigens-including one mAb specific for the spike protein that also recognizes neural tissue. This exploratory immune survey reveals evidence of a compartmentalized and self-reactive immune response in the CNS meriting a more systematic evaluation of neurologically impaired COVID-19 patients., Competing Interests: Competing Interests None of the authors declare interests related to the manuscript.