RESUMO
SARS-CoV-2 mRNA vaccination of healthy individuals is highly immunogenic and protective against severe COVID-19. However, there are limited data on how disease-modifying therapies (DMTs) alter SARS-CoV-2 mRNA vaccine immunogenicity in patients with autoimmune diseases. Here we investigated the induction and stability of vaccine-specific antibodies, B cells, and T cells in multiple sclerosis (MS) patients on different DMTs in a prospective cohort study up to 6 months after homologous prime-boost mRNA vaccination. We analysed 103 MS patients of which 86 received anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-{beta}, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and compared them to 17 untreated MS patients. In contrast to all other DMTs and untreated patients, treatment with aCD20-BCD or fingolimod significantly reduced anti-S1 IgG, serum neutralizing activity, and RBD- and S2-specific B cells. MS patients receiving fingolimod additionally lacked S1- and S2-reactive CD4+ T cell responses. The duration of fingolimod treatment, rather than peripheral blood B and T cell counts prior to vaccination, determined whether patients successfully developed humoral immune responses. Fingolimod blocks the ability of immune cells to recirculate and migrate within secondary lymphoid organs demonstrating that functional immune responses require not only immune cells themselves but also access of these cells to the site of inoculation and their unimpeded movement. The absence of humoral and T cell responses in fingolimod-treated MS patients suggests that these patients are at risk for severe SARS-CoV-2 infections despite vaccination, which is highly relevant for clinical decision-making and adapted protective measures, particularly in light of additional recently approved S1P receptor antagonists for MS treatment.
RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a rapidly unfolding pandemic, overwhelming health care systems worldwide1. Clinical manifestations of Coronavirus-disease 2019 (COVID-19) vary broadly, ranging from asymptomatic infection to acute respiratory failure and death2, yet the underlying mechanisms for this high variability are still unknown. Similarly, the role of host immune responses in viral clearance of COVID-19 remains unresolved. For SARS-CoV (2002/03), however, it has been reported that CD4+ T cell responses correlated with positive outcomes3,4, whereas T cell immune responses to SARS-CoV-2 have not yet been characterized. Here, we describe an assay that allows direct detection and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood. We demonstrate the presence of S-reactive CD4+ T cells in 83% of COVID-19 patients, as well as in 34% of SARS-CoV-2 seronegative healthy donors (HD), albeit at lower frequencies. Strikingly, S-reactive CD4+ T cells in COVID-19 patients equally targeted N-terminal and C-terminal epitopes of S whereas in HD S-reactive CD4+ T cells reacted almost exclusively to the C-terminal epitopes that are a) characterized by higher homology with spike glycoprotein of human endemic "common cold" coronaviruses (hCoVs), and b) contains the S2 subunit of S with the cytoplasmic peptide (CP), the fusion peptide (FP), and the transmembrane domain (TM) but not the receptor-binding domain (RBD). In contrast to S-reactive CD4+ T cells in HD, S-reactive CD4+ T cells from COVID-19 patients co-expressed CD38 and HLA-DR, indivative of their recent in vivo activation. Our study is the first to directly measure SARS-CoV-2-reactive T cell responses providing critical tools for large scale testing and characterization of potential cross-reactive cellular immunity to SARS-CoV-2. The presence of pre-existing SARS-CoV-2-reactive T cells in a subset of SARS-CoV-2 naive HD is of high interest but larger scale prospective cohort studies are needed to assess whether their presence is a correlate of protection or pathology for COVID-19. Results of such studies will be key for a mechanistic understanding of the SARS-CoV-2 pandemic, adaptation of containment methods and to support vaccine development.
