ABSTRACT
Background: Immunosuppressive therapies may impact immune response to COVID-19 vaccines in persons with multiple sclerosis (pwMS). Accordingly, effects of vaccination in pwMS treated with disease-modifying therapies (DMTs) need further elucidation. Aim(s): To investigate COVID-19 BNT162b2 vaccine effect concerning antibody seroconversion, T cells-associated cytokines production and immunophenotype assessment in pwMS under three different DMTs: cladribine, fingolimod, ocrelizumab. Method(s): Enzyme immunoassay test was used for anti-spike IgG detection in 98 DMTs-treated pwMS completing first vaccination cycle. In a subset of patients (n=47), serum T cells-associated cytokines (GrB, IFN-gamma and TNF-alpha) were quantified using an automatic ELISA (ELLA) and blood immunophenotype was assessed by flow cytometry. ANCOVA followed by post hoc tukey's test was used to compare anti-spike IgG response in the different DMTs, Student's paired t-test was used to evaluate differences between pre- and post-vaccination in pairwise samples and Pearson's correlation was applied to evaluate association between spike-specific IgG antibody titer and lymphocytes count. Result(s): More pwMS treated with ocrelizumab (63%) lacked anti-spike IgG compared to patients treated with cladribine (14%) and fingolimod (20%) (p<0.001). When present, the anti-spike IgG titer in the ocrelizumab group was lower than in cladribine- (p<0.001) and in fingolimod-treated pwMS (p=0.003). No significant differences in lymphocytes count and T-cell associated cytokines were observed in cladribine- and in fingolimod-treated pwMS, while in pwMS on ocrelizumab a significant increase in GrB serum levels (p=0.021) and a trend of increased CD4+ T cells count were observed after vaccination. Specifically considering non-seroconverted ocrelizumab-treated pwMS, a significant increase of GrB serum levels (p=0.008) and of CD4+ T lymphocytes count (p=0.040) was foundafter vaccination and a negative correlation was observed between anti-spike IgG production and CD4+T cells count (rho=-0.452, p=0.014). Conclusion(s): Our data confirmed differences in spike-specific antibodies among different DMTs and provided evidence of T-cell immunity preservation and activations after BNT162b2 vaccination in ocrelizumab-treated pwMS, specifically in pwMS patients lacking anti-spike IgG, suggesting a protective T-cell response that might explain why the ongoing treatment with ocrelizumab is not associated with a higher risk of COVID-19 infection.
ABSTRACT
Introduction: The SARS-CoV-2 pandemic has raised, among others, a particular concern for people taking immune-suppressants. The Italian MS Foundation (FISM), Neuroimmunology Association (AINI), Neurological Society (SIN), and MS Registry have constituted an Alliance to tackle these issues. In the field of multiple sclerosis, several reports have suggested a higher risk of infection and an increased severity of the disease in persons treated with anti-CD20 monoclonal antibody. Serological investigations, showing a blunted production of anti-SARS-CoV-2 antibodies, questioned the usefulness of vaccination in these subjects, without, however, considering T cell responses. Objectives and Aims: To investigate antiviral T cell responses after infection with SARS-CoV-2 in persons with MS (pwMS) treated with Ocrevus.Control groups include pwMS treated with Ocrevus without SARS-CoV-2 infection, persons without MS with SARS-CoV-2 infection, and healthy individuals vaccinated or not with BNT16b2. Methods: Blood samples were collected and processed to isolate PBMCs, that were then stored frozen. PBMCs were stimulated with SARS-CoV-2 peptide pools and T cell reactivity was assessed by ELISPOT for IFNg detection, and by multiparametric FACS analyses for assessment and characterization of T cell activation. Results: ELISPOT assay against the spike and the N protein of SARS-CoV-2 displayed specific T cell reactivity in 80% pwMS treated with Ocrevus and infected by SARS-CoV-2, similar to infected persons without MS. FACS analysis following stimulation with SARS-CoV-2 peptide pools, showed the presence of activation-induced markers (AIM) in both CD4 and CD8 T cell subsets in 96% and 92% of these individuals, respectively. CD4 AIM+ cells were mostly central and effector memory cells, while CD8 cells were largely CD45RA+ terminally differentiated effectors (TEMRA) and poised for cytotoxicity, with a significant fraction of naïve cells. Within naïve AIM+ CD4 and CD8 cells we detected memory stem cells, suggesting the acquisition of long-term memory and protection from reinfection. COVID-19- recovered pwMS treated with Ocrevus had T cell responses comparable to healthy individuals vaccinated with BNT162b2, particularly concerning the ability to produce cytokines. Conclusions: B-cell depletion using Ocrevus does not impair the development of anti-SARS-CoV-2 T cell responses. Multistakeholder initiatives are mandatory to rapidly obtain unbiased clinically crucial information.