SARS-CoV-2 mRNA vaccinations fail to elicit humoral and cellular immune responses in patients with multiple sclerosis receiving fingolimod

Abstract

BackgroundSARS-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.MethodsAs part of a prospective cohort study, we investigated the induction, stability and boosting of vaccine-specific antibodies, B cells and T cells in patients with multiple sclerosis (MS) on different DMTs after homologous primary, secondary and booster SARS-CoV-2 mRNA vaccinations. Of 126 patients with MS analysed, 105 received either anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-β, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and 21 were untreated MS patients for comparison.ResultsIn contrast to all other MS patients, and even after booster, most aCD20-BCD- and fingolimod-treated patients showed no to markedly reduced anti-S1 IgG, serum neutralising activity and a lack of receptor binding domain-specific and S2-specific B cells. Patients receiving fingolimod additionally lacked spike-reactive CD4+ T cell responses. The duration of fingolimod treatment, rather than peripheral blood B and T cell counts prior to vaccination, determined whether a humoral immune response was elicited.ConclusionsThe lack of immunogenicity under long-term fingolimod treatment demonstrates 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 suggests that fingolimod-treated patients with MS are at risk for severe SARS-CoV-2 infections despite booster vaccinations, which is highly relevant for clinical decision-making and adapted protective measures, particularly considering additional recently approved sphingosine-1-phosphate receptor antagonists for MS treatment.

Longitudinal characterisation of B and T-cell immune responses after the booster dose of COVID-19 mRNA-vaccine in people with multiple sclerosis using different disease-modifying therapies

“…In PwMS, the SARS-CoV-2 vaccine booster dose increases antibody titers according to therapy 17 18. Indeed, evidence show that the booster does not improve the already low serological response in those under fingolimod or ocrelizumab treatments, and neither the impaired cellular responses of patients under fingolimod therapy 13 19 20. Similarly, in ocrelizumab-treated patients SARS-CoV-2 booster dose has no additive effect on the maximal T-cell response observed after the first vaccination cycle 21.…”

The impact of sphingosine-1-phosphate receptor modulators on COVID-19 and SARS-CoV-2 vaccination

“…Therefore, ways to improve/optimize vaccination responses will be beneficial ( Sullivan et al, 2022 *). Although, repeated boosting can increase the titres of SARS-CoV-2 specific-antibodies in some people ( Tallantyre et al, 2022a , Milo et al, 2022 , Capuano et al, 2022 , Achtnichts et al, 2022 ), uninterrupted S1PR modulator treatment is currently often associated with a blunted vaccination response ( Pitzalis et al, 2021 , Tallantyre et al, 2022a , Louapre et al, 2022 *), ( Meyer-Arndt et al, 2022 , Akgün et al, 2022 *), ( Scn et al, 2022 ). A long-period of fingolimod discontinuation, to allow recovery of lymphocytes, may increase the chance of a vaccine-induced antibody response, but risks disease breakthrough that can occur within a few weeks of discontinuation ( Barry et al, 2019 , Achtnichts et al, 2022 ).…”

“…Similarly, modest reductions in antibody titres notably with other vaccines, have been seen in fingolimod-treated individuals ( Boulton et al, 2012 , Kappos et al, 2015 , Zoehner et al, 2019 ). However, fingolimod consistently inhibits both seroconversion and peripheral blood T cell responses following SARS-CoV-2 vaccination, although there was some variability between studies in part due to the: individuals, viral strain, past infection, vaccine type; time of assay relative to infection/vaccination, different assays and different functional and physical targets ( Wu et al, 2022 , Gombolay et al, 2022 , Tallantyre et al, 2022a , Tallantyre et al, 2022b , Achiron et al, 2021 , Meyer-Arndt et al, 2022 ). Importantly, this had biological impact because in comparison to other MS treatments, use of either fingolimod or CD20-depleting antibodies was sometimes associated with COVID-19 disease breakthrough following vaccination ( Schiavetti et al, 2022 , Garjani et al, 2022 , Bsteh et al, 2022 , Sormani et al, 2022 ).…”

“…Whilst the majority on SARS-CoV-2 vaccine responses have focused on antibody responses, reduced T-cell recall responses have also repeatedly been reported during fingolimod treatment in many small studies that are perhaps consistent with the induced T cell lymphopenia ( Wu et al, 2022 , Gombolay et al, 2022 , Tallantyre et al, 2022a , Meyer-Arndt et al, 2022 , Wolf et al, 2022 *). The peripheral blood T cell responses in people treated with the more recent S1PR modulators have been inconsistent and further study is required ( Rauser et al, 2022 *), ( Kantor, 2022 *), ( Akgün et al, 2022 *).…”

N2 Year in Review

“…By contrast, patients treated with fingolimod failed to mount T-cell responses to SARS-CoV2 after the second (N = 12) and third (N = 9) vaccinations, a finding in line with another study from Germany. 66 Not surprisingly, the timing of vaccination against SARS-CoV2 in relation to B-cell depletion in pwMS has an effect on cellular and humoral immune responses to the vaccine as shown in a study that included 133 pwMS on anti-CD20 monoclonal antibodies. 67 Vaccination reactogenicity was reported by 719 pwMS who received the AstraZeneca, Pfizer-BioNTech, or Moderna vaccines, using an online people-powered research network (iConquerMS).…”