ABSTRACT
Introduction: MS disease-modifying therapies (DMTs) lead to distinct effects on humoral and cellular immunity. Effective vaccine- elicited immunity to severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2), the causative agent of the ongoing COVID-19 pandemic, requires robust antibody and CD4+ and CD8+ T cell responses against the SARS-CoV-2 spike protein. Understanding how different MS DMTs affect COVID-19 vaccine immunity is a vital clinical gap that needs to be urgently addressed. Objectives: The goal of this study is to assess COVID-19 vaccine- elicited antibody and T cell responses in MS patients on different of DMTs. Aims: To measure SARS-CoV-2 spike antigen-specific antibody and CD4+ and CD8+ T cell responses before and after COVID- 19 vaccination of MS patients on different DMTs. Methods: Enrolment included MS patients on no therapy, or treated with glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NAT), sphingosine-1-phosphate receptor (S1P) modulator, or anti-CD20 monoclonal antibody (mAb). Serum and peripheral blood mononuclear cells (PBMCs) were collected from all patients before and 2-4 weeks following final COVID-19 vaccination. Patient serum was tested on a Luminex bead-based assay to quantitatively measure IgG levels against the whole SARSCoV- 2 spike protein and the spike receptor binding domain (RBD). PBMCs were stimulated with pools of SARS-CoV-2 spike peptides to measure the frequencies of spike-specific CD4+ and CD8+ T cells by activation-induced marker expression. Results: Following COVID-19 vaccination, all untreated MS patients and patients on GA, DMF, and NAT were seropositive with similar high IgG titres to total spike and spike RBD. MS patients on S1P modulators and anti-CD20 mAb exhibited significantly reduced IgG titres to total spike and spike RBD antigens, with only a fraction of patients reaching seropositivity. Spike antigen-specific CD4+ and CD8+ T cell responses were present at similar levels across all DMT categories following COVID-19 vaccination. Conclusions: MS DMTs exhibited differential effects on COVID- 19 vaccine-elicited humoral, but not T cell immunity. Whereas IgG responses were unaffected in MS patients on GA, DMF, and NAT, IgG levels were reduced in MS patients on S1P modulators and anti-CD20 mAb. The findings of this study have important clinical implications for assessing potential risk of COVID-19 infection in vaccinated MS patients on specific DMTs.
ABSTRACT
Background: 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. Methods: We examined immune parameters in CSF and blood samples from a cohort of hospitalized patients with COVID-19 and significant neurological complications (n=6), compared to SARS-CoV-2 uninfected controls (Fig1A). Immune cells were characterized by single cell RNA and repertoire sequencing. Intrathecal antibodies were assessed for anti-viral and auto-reactivity by ELISA, mouse brain immunostaining, phage display, and IP-MS. Results: Through single cell and parallel cytokine analyses of CSF and paired plasma, we found divergent T cell responses in the CNS compartment, including increased levels of IL-1B and IL-12-associated innate and adaptive immune cell activation (Fig1B). We found evidence of clonal expansion of B cells in the CSF, with B cell receptor sequences that were unique from those observed in peripheral blood B cells (Fig1C), suggesting a divergent intrathecal humoral response to SARS-CoV-2. Indeed, all COVID-19 cases examined had anti-SARS-antibodies. Next, we directly examined whether CSF resident antibodies targeted self-antigens and found a significant burden of CNS autoimmunity, with the CSF from most patients recognizing neural self-antigens. COVID-19 CSF produced immunoreactive staining of specific anatomic regions of the brain including cortical neurons, olfactory bulb, thalamus, and cerebral vasculature. Finally, we produced a panel of monoclonal antibodies from patients' CSF and peripheral blood, and show that these target both anti-viral and anti-neural antigens-including one CSF-derived mAb specific for the spike protein that also recognizes neural tissue (Fig1D). Conclusion: This immune survey reveals evidence of a compartmentalized and self-reactive immune response in the CNS in COVID-19 patients with neurologic symptoms. We identified both innate and adaptive anti-viral immune responses, as well as humoral autoimmunity that appears to be unique to the CNS during SARS-CoV-2 infection. These data suggest a potential role for autoimmunity in contributing to neurological symptoms, and merit further investigation to the potential role of autoantibodies in post-acute COVID-19 neurological symptoms.