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

  • Author Footnotes
    1 Equal contribution.
    David Baker
    Correspondence
    Corresponding author.
    Footnotes
    1 Equal contribution.
    Affiliations
    Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
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  • Author Footnotes
    1 Equal contribution.
    Eugenia Forte
    Footnotes
    1 Equal contribution.
    Affiliations
    Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
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  • Gareth Pryce
    Affiliations
    Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
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  • Angray S. Kang
    Affiliations
    Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom

    Centre for Oral Immunobiology and Regenerative Medicine, Dental Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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  • Louisa K. James
    Affiliations
    Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
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  • Gavin Giovannoni
    Affiliations
    Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom

    Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
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  • Klaus Schmierer
    Affiliations
    Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom

    Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
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  • Author Footnotes
    1 Equal contribution.
Open AccessPublished:November 21, 2022DOI:https://doi.org/10.1016/j.msard.2022.104425

      Highlights

      • Treatment with fingolimod is not associated with a worse prognosis from COVID-19.
      • Fingolimod inhibits antibody and measureable T cell responses due to SARS-COV-2 vaccination.
      • Fingolimod seems to reduce seroconversion compared to other S1PR modulators.
      • Vaccine antibody responses are probably controlled by S1PR1, S1PR2 and S1PR4.
      • Fingolimod/ozanimod/ponesimod/siponimod should not limit current anti-viral agents.+.

      Abstract

      Background

      Sphingosine-one phosphate receptor (S1PR) modulation inhibits S1PR1-mediated lymphocyte migration, lesion formation and positively-impacts on active multiple sclerosis (MS). These S1PR modulatory drugs have different: European Union use restrictions, pharmacokinetics, metabolic profiles and S1PR receptor affinities that may impact MS-management. Importantly, these confer useful properties in dealing with COVID-19, anti-viral drug responses and generating SARS-CoV-2 vaccine responses.

      Objective

      To examine the biology and emerging data that potentially underpins immunity to the SARS-CoV-2 virus following natural infection and vaccination and determine how this impinges on the use of current sphingosine-one-phosphate modulators used in the treatment of MS.

      Methods

      A literature review was performed, and data on infection, vaccination responses; S1PR distribution and functional activity was extracted from regulatory and academic information within the public domain.

      Observations

      Most COVID-19 related information relates to the use of fingolimod. This indicates that continuous S1PR1, S1PR3, S1PR4 and S1PR5 modulation is not associated with a worse prognosis following SARS-CoV-2 infection. Whilst fingolimod use is associated with blunted seroconversion and reduced peripheral T-cell vaccine responses, it appears that people on siponimod, ozanimod and ponesimod exhibit stronger vaccine-responses, which could be related notably to a limited impact on S1PR4 activity. Whilst it is thought that S1PR3 controls B cell function in addition to actions by S1PR1 and S1PR2, this may be species-related effect in rodents that is not yet substantiated in humans, as seen with bradycardia issues. Blunted antibody responses can be related to actions on B and T-cell subsets, germinal centre function and innate-immune biology. Although S1P1R-related functions are seeming central to control of MS and the generation of a fully functional vaccination response; the relative lack of influence on S1PR4-mediated actions on dendritic cells may increase the rate of vaccine-induced seroconversion with the newer generation of S1PR modulators and improve the risk-benefit balance

      Implications

      Although fingolimod is a useful asset in controlling MS, recently-approved S1PR modulators may have beneficial biology related to pharmacokinetics, metabolism and more-restricted targeting that make it easier to generate infection-control and effective anti-viral responses to SARS-COV-2 and other pathogens. Further studies are warranted.

      Graphical abstract

      Keywords

      Abbreviations:

      a.u (arbitrary units), COVID-19 (coronavirus 2019), Cmax (maximum concentration), CNS (central nervous system), mRNA (messenger ribonucleic acid), MS (Multiple sclerosis), SAR-CoV-2 (severe acute respiratory corona virus two), S1PR (sphingosine-1-phosphate receptor, SmPC, Summary of Medical Product Characteristics), ELISA (enzyme-linked immunosorbent assay), ECLIA (electrochemiluminescent immunoassay), CLIA (chemiluminescent immunoassay)

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      • Pelletier J.
      • Cordioli C.
      • Vukusic S.
      • Moiola L.
      • Kerschen P.
      • Radaelli M.
      • Théaudin M.
      • Immovilli P.
      • Casez O.
      • Capobianco M.
      • Ciron J.
      • Trojano M.
      • Stankoff B.
      • Créange A.
      • Tedeschi G.
      • Clavelou P.
      • Comi G.
      • Thouvenot E.
      • Battaglia M.A.
      • Moreau T.
      • Patti F.
      • De Sèze J.
      • Louapre C.
      Musc-19Covisep study groups
      DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France.
      ;
      • Simpson-Yap S.
      • De Brouwer E.
      • Kalincik T.
      • Rijke N.
      • Hillert J.A.
      • Walton C.
      • Edan G.
      • Moreau Y.
      • Spelman T.
      • Geys L.
      • Parciak T.
      • Gautrais C.
      • Lazovski N.
      • Pirmani A.
      • Ardeshirdavanai A.
      • Forsberg L.
      • Glaser A.
      • McBurney R.
      • Schmidt H.
      • Bergmann A.B.
      • Braune S.
      • Stahmann A.
      • Middleton R.
      • Salter A.
      • Fox R.J.
      • van der Walt A.
      • Butzkueven H.
      • Alroughani R.
      • Ozakbas S.
      • Rojas J.I.
      • van der Mei I.
      • Nag N.
      • Ivanov R.
      • Sciascia do Olival G.
      • Dias A.E.
      • Magyari M.
      • Brum D.
      • Mendes M.F.
      • Alonso R.N.
      • Nicholas R.S.
      • Bauer J.
      • Chertcoff A.S.
      • Zabalza A.
      • Arrambide G.
      • Fidao A.
      • Comi G.
      • Peeters L.
      Associations of disease-modifying therapies with COVID-19 severity in multiple sclerosis.
      ;
      • Simpson-Yap S.
      • Pirmani A.
      • Kalincik T.
      • De Brouwer E.
      • Geys L.
      • Parciak T.
      • Helme A.
      • Rijke N.
      • Hillert J.A.
      • Moreau Y.
      • Edan G.
      • Sharmin S.
      • Spelman T.
      • McBurney R.
      • Schmidt H.
      • Bergmann A.B.
      • Braune S.
      • Stahmann A.
      • Middleton R.M.
      • Salter A.
      • Bebo B.
      • Van der Walt A.
      • Butzkueven H.
      • Ozakbas S.
      • Boz C.
      • Karabudak R.
      • Alroughani R.
      • Rojas J.I.
      • van der Mei I.A.
      • Sciascia do Olival G.
      • Magyari M.
      • Alonso R.N.
      • Nicholas R.S.
      • Chertcoff A.S.
      • de Torres A.Z.
      • Arrambide G.
      • Nag N.
      • Descamps A.
      • Costers L.
      • Dobson R.
      • Miller A.
      • Rodrigues P.
      • Prčkovska V.
      • Comi G.
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      Neutralizing antibodies against the SARS-CoV-2 Omicron variant BA.1 following homologous and heterologous CoronaVac or BNT162b2 vaccination.
      ;
      • Tuekprakhon A.
      • Nutalai R.
      • Dijokaite-Guraliuc A.
      • Zhou D.
      • Ginn H.M.
      • Selvaraj M.
      • Liu C.
      • Mentzer A.J.
      • Supasa P.
      • Duyvesteyn H.M.E.
      • Das R.
      • Skelly D.
      • Ritter T.G.
      • Amini A.
      • Bibi S.
      • Adele S.
      • Johnson S.A.
      • Constantinides B.
      • Webster H.
      • Temperton N.
      • Klenerman P.
      • Barnes E.
      • Dunachie S.J.
      • Crook D.
      • Pollard A.J.
      • Lambe T.
      • Goulder P.
      • Paterson N.G.
      • Williams M.A.
      • Hall D.R.
      • Fry E.E.
      • Huo J.
      • Mongkolsapaya J.
      • Ren J.
      • Stuart D.I.
      • Screaton G.R
      OPTIC ConsortiumISARIC4C Consortium
      Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum.
      ). As this breakthrough was associated with agents with poor seroconversion, it supports the view that viral neutralizing antibodies are particularly important in preventing infection/re-infection (
      • Baker D.
      • Amor S.
      • Kang A.S.
      • Schmierer K.
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ;
      • Sormani M.P.
      • Schiavetti I.
      • Inglese M.
      • Carmisciano L.
      • Laroni A.
      • Lapucci C.
      • Visconti V.
      • Serrati C.
      • Gandoglia I.
      • Tassinari T.
      • Perego G.
      • Brichetto G.
      • Gazzola P.
      • Mannironi A.
      • Stromillo M.L.
      • Cordioli C.
      • Landi D.
      • Clerico M.
      • Signoriello E.
      • Cocco E.
      • Frau J.
      • Ferrò M.T.
      • Di Sapio A.
      • Pasquali L.
      • Ulivelli M.
      • Marinelli F.
      • Pizzorno M.
      • Callari G.
      • Iodice R.
      • Liberatore G.
      • Caleri F.
      • Repice A.M.
      • Cordera S.
      • Battaglia M.A.
      • Salvetti M.
      • Franciotta D.
      • Uccelli A.
      CovaXiMS study group
      Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.
      ). This indicates that the clinical responses observed can be attributed to the chemistry and biology of the different agents. It therefore remained to be seen whether there could be any differences between fingolimod and the other sphingosine-one-phosphate receptor (S1PR) modulators, approved shortly before or during the COVID-19 pandemic (Fig. 1) (
      • Al-Salama Z.T.
      • Siponimod
      First global approval.
      ;
      • Lamb Y.N.
      Ozanimod: first Approval.
      ;
      • Markham A.
      Ponesimod: first approval.
      ), which may predict or explain likely COVID-19 infection and vaccine responses that may affect the risk-benefit balance.
      Fig. 1
      Fig. 1Sphinogsine-1-phosphate receptor modulators used in multiple sclerosis. Chemical structures, relative elimination half-lives, the presence of active metabolites (M) and receptor binding and distribution profiles were obtaining from the Summary of Medical Product Characteristic reported at the European Medicines Agency website and the literature. Ponesimod has low affinity for S1PR5. Created with Biorender.com.

      3. Sphingosine-one-phosphate receptor modulators used in multiple sclerosis

      Migration-inhibition ultimately limits entry of pathogenic cells into the CNS, which is an effective strategy to control relapsing MS (
      • Dobson R.
      • Giovannoni G.
      Multiple sclerosis - a review.
      ;
      • Lohmann L.
      • Janoschka C.
      • Schulte-Mecklenbeck A.
      • Klinsing S.
      • Kirstein L.
      • Hanning U.
      • Wirth T.
      • Schneider-Hohendorf T.
      • Schwab N.
      • Gross C.C.
      • Eveslage M.
      • Meuth S.G.
      • Wiendl H.
      • Klotz L.
      Immune cell profiling during switching from natalizumab to fingolimod reveals differential effects on systemic immune-regulatory networks and on trafficking of non-t cell populations into the cerebrospinal fluid-results from the ToFingo Successor Study.
      ). Sphingosine-1-phosphate acts via a number of G-protein-coupled S1P receptors (Fig. 1, Table 2). Fingolimod is likewise phosphorylated by sphingosine kinase enzymes to create an active molecule that performs important signalling function related notably to the vascular and immune systems (
      • Scott L.J.
      Fingolimod: a review of its use in the management of relapsing-remitting multiple sclerosis.
      ;
      • Grassi S.
      • Mauri L.
      • Prioni S.
      • Cabitta L.
      • Sonnino S.
      • Prinetti A.
      • Giussani P.
      Sphingosine 1-phosphate receptors and metabolic enzymes as druggable targets for brain diseases.
      ). Different levels of S1P within tissues, lymph and the circulation and different cellular expression profiles of the S1PR creates gradients that can effect migration and influence the biology of cells (
      • Cyster J.G.
      • Schwab S.R.
      Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.
      ). The current S1PR modulators have distinct S1PR binding affinities, pharmacokinetics and different use-indications (Fig. 1).
      In the United States of America: fingolimod, siponimod, ozanimod and ponesimod all have a similar utility and are licensed for clinically-isolated syndrome, relapsing MS and active secondary progressive MS (
      • Al-Salama Z.T.
      • Siponimod
      First global approval.
      ;
      • Lamb Y.N.
      Ozanimod: first Approval.
      ;
      • Markham A.
      Ponesimod: first approval.
      ;
      • Scott L.J.
      Fingolimod: a review of its use in the management of relapsing-remitting multiple sclerosis.
      ). These are all characterised by bout attacks and/or new T2 or gadolinium enhancing T1 lesion formation (
      • Lublin F.D.
      • Reingold S.C.
      • Cohen J.A.
      • Cutter G.R.
      • Sørensen P.S.
      • Thompson A.J.
      • Wolinsky J.S.
      • Balcer L.J.
      • Banwell B.
      • Barkhof F.
      • Bebo Jr, B.
      • Calabresi P.A.
      • Clanet M.
      • Comi G.
      • Fox R.J.
      • Freedman M.S.
      • Goodman A.D.
      • Inglese M.
      • Kappos L.
      • Kieseier B.C.
      • Lincoln J.A.
      • Lubetzki C.
      • Miller A.E.
      • Montalban X.
      • O'Connor P.W.
      • Petkau J.
      • Pozzilli C.
      • Rudick R.A.
      • Sormani M.P.
      • Stüve O.
      • Waubant E.
      • Polman C.H
      Defining the clinical course of multiple sclerosis: the 2013 revisions.
      ). However, in Europe, differences in the licensing exist that may influence use in practice. As such, fingolimod is a second-line treatment for highly-active relapsing MS, siponimod is licenced for active, secondary progressive MS, whereas both ozanimod and ponesimod have recently been approved as first-line treatments for active relapsing MS (
      • Al-Salama Z.T.
      • Siponimod
      First global approval.
      ;
      • Lamb Y.N.
      Ozanimod: first Approval.
      ;
      • Markham A.
      Ponesimod: first approval.
      ;
      • Scott L.J.
      Fingolimod: a review of its use in the management of relapsing-remitting multiple sclerosis.
      ). Fingolimod has been used and studied most extensively and forms the basis for most COVID-19- related information. Fingolimod exhibits a long half-life and so peripheral lymphocyte recover slowly after treatment cessation (Table 1). However, once cells repopulate, disease may relapse and therefore this requires an appropriately-timed switch to an alternative treatment (
      • Barry B.
      • Erwin A.A.
      • Stevens J.
      • Tornatore C.
      Fingolimod rebound: a review of the clinical experience and management considerations.
      ). Although there were initial recommendations to stop fingolimod treatment following SARS-CoV-2 infection, the virus would be naturally cleared before therapeutic levels have been eliminated (
      • Baker D.
      • Amor S.
      • Kang A.S.
      • Schmierer K.
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ). This probably prompted some people to switch to S1PR modulators with a more rapid clearance, in case people exhibited COVID-19 symptoms.
      Table 1Biological and pharmacokinetic characteristics of S1PR modulators.
      TreatmentS1PR targetedTime to CmaxApproximate Elimination half-liveMedian time lymphocyte recovery
      Ponesimod12–4h33 h1 week
      Siponimod1,54h30 h10 days
      Ozanimod1,56–8h21 h/11days(CC112273)30 days
      Fingolimod1,3,4,512–26h6–9days1–2 months
      Information about the pharmacokinetics of sphinogsine-1-phosphate receptor (S1PR) modulators were obtained from the Summary of Medical Product Characteristics from the European Medicines Agency website. CC112273 is a metabolite of ozanimod. Cmax maximum concentration
      Siponimod, ozanimod and ponesimod have relatively short half-lives compared to fingolimod (Table 1) (
      • Gardin A.
      • Ufer M.
      • Legangneux E.
      • Rossato G.
      • Jin Y.
      • Su Z.
      • Pal P.
      • Li W.
      • Shakeri-Nejad K
      Effect of fluconazole coadministration and CYP2C9 genetic polymorphism on siponimod pharmacokinetics in healthy subjects.
      ;
      • Brossard P.
      • Derendorf H.
      • Xu J.
      • Maatouk H.
      • Halabi A.
      • Dingemanse J.
      Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study.
      ;
      • Surapaneni S.
      • Yerramilli U.
      • Bai A.
      • Dalvie D.
      • Brooks J.
      • Wang X.
      • Selkirk J.V.
      • Yan Y.G.
      • Zhang P.
      • Hargreaves R.
      • Kumar G.
      • Palmisano M.
      • Tran J.Q.
      Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator.
      ), although individuals with the slow-metabolising cytochrome P450 variants for CYP2C9 (variant *3) are screened and excluded prior to commencement of siponimod treatment (
      • Al-Salama Z.T.
      • Siponimod
      First global approval.
      ;
      • Gardin A.
      • Ufer M.
      • Legangneux E.
      • Rossato G.
      • Jin Y.
      • Su Z.
      • Pal P.
      • Li W.
      • Shakeri-Nejad K
      Effect of fluconazole coadministration and CYP2C9 genetic polymorphism on siponimod pharmacokinetics in healthy subjects.
      ). Furthermore, as ozanimod is metabolised to compounds with long half-lives, it will exhibit similar issues to fingolimod in terms of slow lymphocyte recovery following treatment cessation (Table 2) (
      • Lamb Y.N.
      Ozanimod: first Approval.
      ;
      • Surapaneni S.
      • Yerramilli U.
      • Bai A.
      • Dalvie D.
      • Brooks J.
      • Wang X.
      • Selkirk J.V.
      • Yan Y.G.
      • Zhang P.
      • Hargreaves R.
      • Kumar G.
      • Palmisano M.
      • Tran J.Q.
      Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator.
      ). In contrast ponesimod has a relatively short life, with a relatively rapid repopulation of lymphocytes (Table 1) (
      • Valenzuela B.
      • Pérez-Ruixo J.J.
      • Leirens Q.
      • Ouwerkerk-Mahadevan S.
      • Poggesi I.
      Effect of ponesimod exposure on total lymphocyte dynamics in patients with multiple sclerosis.
      ) and therefore could offer advantages following infection or in using short treatment breaks to promote better vaccination responses. However, information on the time window before disease reactivation occurs after cessation is currently limited (
      • Lublin F.
      • Ait-Tihyaty M.
      • Keenan A.
      • Gandhi K.
      • Turkoz I.
      • Sidorenko T.
      • Wong J.
      • Kappos L.
      Disease activity after short-term interruption of ponesimod versus teriflunomide in relapsing multiple sclerosis patients. P386.
      ), but effective vaccination following discontinuation that avoids disease breakthrough seems feasible with short-half live agents (
      • Ufer M.
      • Shakeri-Nejad K.
      • Gardin A.
      • Su Z.
      • Paule I.
      • Marbury T.C.
      • Legangneux E
      Impact of siponimod on vaccination response in a randomized, placebo-controlled study.
      ;
      • Ziemssen T.
      • Groth M.
      • Rauser B.
      • Bopp T.
      Assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod-treated patients: a nonrandomized controlled clinical trial (AMA-VACC).
      ,
      • Spiller K.
      • Aras R.
      • DeGuzman M.
      • Ramsburg E.
      • Bhattacharya A.
      A short pause in ponesimod treatment completely restores the ability to mount post-vaccination antibody titers in mice P646.
      ).
      Table 2Receptors specific cities of approved S1PR modulators.
      TreatmentSphingosine-1-phophate (S1P) receptor binding affinities
      S1PR1S1PR2S1PR3S1PR4S1PR5Reference
      S1P0.47nM
      competitive radio-ligand binding.
      0.31nM
      competitive radio-ligand binding.
      0.17nM
      competitive radio-ligand binding.
      95 nM
      competitive radio-ligand binding.
      0.61nM
      competitive radio-ligand binding.
      • Mandala S.
      • Hajdu R.
      • Bergstrom J.
      • Quackenbush E.
      • Xie J.
      • Milligan J.
      • Thornton R.
      • Shei G.J.
      • Card D.
      • Keohane C.
      • Rosenbach M.
      • Hale J.
      • Lynch C.L.
      • Rupprecht K.
      • Parsons W.
      • Rosen H.
      Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
      Fingolimod300nM
      competitive radio-ligand binding.
      >10,000nM
      competitive radio-ligand binding.
      >10,000nM
      competitive radio-ligand binding.
      >5,000nM
      competitive radio-ligand binding.
      2623nM
      competitive radio-ligand binding.
      Fingolimod-P0.21nM
      competitive radio-ligand binding.
      >10,000nM
      competitive radio-ligand binding.
      5.0nM
      competitive radio-ligand binding.
      5.9 nM
      competitive radio-ligand binding.
      0.59nM
      competitive radio-ligand binding.
      Fingolimod-P8.2nM
      gamma GTPS or.
      >10,000nM
      gamma GTPS or.
      8.4nM
      gamma GTPS or.
      7.2nM
      gamma GTPS or.
      8.2nM
      gamma GTPS or.
      • Brinkmann V.
      • Davis M.D.
      • Heise C.E.
      • Albert R.
      • Cottens S.
      • Hof R.
      • Bruns C.
      • Prieschl E.
      • Baumruker T.
      • Hiestand P.
      • Foster C.A.
      • Zollinger M.
      • Lynch K.R.
      The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
      Siponimod0.39nM
      gamma GTPS or.
      >10,000nM
      gamma GTPS or.
      > 1,000nM
      gamma GTPS or.
      750nM
      gamma GTPS or.
      0.98nM
      gamma GTPS or.
      • Gergely P.
      • Nuesslein-Hildesheim B.
      • Guerini D.
      • Brinkmann V.
      • Traebert M.
      • Bruns C.
      • Pan S.
      • Gray N.S.
      • Hinterding K.
      • Cooke N.G.
      • Groenewegen A.
      • Vitaliti A.
      • Sing T.
      • Luttringer O.
      • Yang J.
      • Gardin A.
      • Wang N.
      • Crumb Jr, W.J.
      • Saltzman M.
      • Rosenberg M.
      • Wallström E.
      The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate.
      OzanimodFingolimod-P0.41nM
      gamma GTPS or.
      >10,000nM
      gamma GTPS or.
      >10,000nM
      gamma GTPS or.
      >7,865nM
      beta-arrestin binding assays.
      11nM
      gamma GTPS or.
      • Scott F.L.
      • Clemons B.
      • Brooks J.
      • Brahmachary E.
      • Powell R.
      • Dedman H.
      • Desale H.G.
      • Timony G.A.
      • Martinborough E.
      • Rosen H.
      • Roberts E.
      • Boehm M.F.
      • Peach R.J.
      Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity.
      Siponimod0.27nM
      gamma GTPS or.
      >10,000nM
      gamma GTPS or.
      0.90nM
      gamma GTPS or.
      345nM
      beta-arrestin binding assays.
      0.5nM
      gamma GTPS or.
      0.39nM
      gamma GTPS or.
      >10,000nM
      gamma GTPS or.
      >10,000nM
      gamma GTPS or.
      920nM
      beta-arrestin binding assays.
      0.38nM
      gamma GTPS or.
      Ponesimod5.7nM
      gamma GTPS or.
      >10,000nM
      gamma GTPS or.
      105nMa
      gamma GTPS or.
      1,108nM
      gamma GTPS or.
      ,
      Maximal effect at 10,000 nM on S1PR4/S1PR5 was 18/42%, respectively of the effect on S1P response, so was not only less efficacious but also less potent than S1P. The standard daily doses are: 0.5 mg fingolimod, 1 mg siponimod, 0.92 mg ozanimod or 20 mg ponesimod.
      59.1nM
      gamma GTPS or.
      ,
      Maximal effect at 10,000 nM on S1PR4/S1PR5 was 18/42%, respectively of the effect on S1P response, so was not only less efficacious but also less potent than S1P. The standard daily doses are: 0.5 mg fingolimod, 1 mg siponimod, 0.92 mg ozanimod or 20 mg ponesimod.
      • Bolli M.H.
      • Abele S.
      • Binkert C.
      • Bravo R.
      • Buchmann S.
      • Bur D.
      • Gatfield J.
      • Hess P.
      • Kohl C.
      • Mangold C.
      • Mathys B.
      • Menyhart K.
      • Müller C.
      • Nayler O.
      • Scherz M.
      • Schmidt G.
      • Sippel V.
      • Steiner B.
      • Strasser D.
      • Treiber A.
      • Weller T.
      2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists.
      S1P25.3nM
      gamma GTPS or.
      43.9M
      gamma GTPS or.
      0.7nM
      gamma GTPS or.
      164nM
      gamma GTPS or.
      1.1nM
      gamma GTPS or.
      The S1P1R binding affinities of sphinogsine-1-phosphate (S1P) and the S1PR modulators were extracted from the literature. The results report the aIC50 or b,cEC50 binding levels using either.
      a competitive radio-ligand binding.
      b gamma GTPS or.
      c beta-arrestin binding assays.
      d Maximal effect at 10,000 nM on S1PR4/S1PR5 was 18/42%, respectively of the effect on S1P response, so was not only less efficacious but also less potent than S1P. The standard daily doses are: 0.5 mg fingolimod, 1 mg siponimod, 0.92 mg ozanimod or 20 mg ponesimod.
      Fingolimod binds to S1PR1, S1PR3, S1PR4, and S1PR5, which have distinct tissue distributions that will impact on its function (Fig. 1; Table 2) (
      • Brinkmann V.
      • Davis M.D.
      • Heise C.E.
      • Albert R.
      • Cottens S.
      • Hof R.
      • Bruns C.
      • Prieschl E.
      • Baumruker T.
      • Hiestand P.
      • Foster C.A.
      • Zollinger M.
      • Lynch K.R.
      The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
      ). However, it is clear that the major therapeutic impact on lymphocyte migration is mediated by S1PR1 (
      • Sanna M.G.
      • Liao J.
      • Jo E.
      • Alfonso C.
      • Ahn M.Y.
      • Peterson M.S.
      • Webb B.
      • Lefebvre S.
      • Chun J.
      • Gray N.
      • Rosen H
      Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate.
      ). Ponesimod targets largely S1PR1, with lower affinities and partial activity for other receptors, notably S1PR5, and inhibits relapsing MS (Fig. 1, Table 2) (
      • Markham A.
      Ponesimod: first approval.
      ;
      • Bolli M.H.
      • Abele S.
      • Binkert C.
      • Bravo R.
      • Buchmann S.
      • Bur D.
      • Gatfield J.
      • Hess P.
      • Kohl C.
      • Mangold C.
      • Mathys B.
      • Menyhart K.
      • Müller C.
      • Nayler O.
      • Scherz M.
      • Schmidt G.
      • Sippel V.
      • Steiner B.
      • Strasser D.
      • Treiber A.
      • Weller T.
      2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists.
      ). Siponimod and ozanimod both target S1P1R and S1PR5, to notably to limit perceived S1PR3-mediated side effects encountered with fingolimod (
      • Gergely P.
      • Nuesslein-Hildesheim B.
      • Guerini D.
      • Brinkmann V.
      • Traebert M.
      • Bruns C.
      • Pan S.
      • Gray N.S.
      • Hinterding K.
      • Cooke N.G.
      • Groenewegen A.
      • Vitaliti A.
      • Sing T.
      • Luttringer O.
      • Yang J.
      • Gardin A.
      • Wang N.
      • Crumb Jr, W.J.
      • Saltzman M.
      • Rosenberg M.
      • Wallström E.
      The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate.
      ;
      • Sanna M.G.
      • Liao J.
      • Jo E.
      • Alfonso C.
      • Ahn M.Y.
      • Peterson M.S.
      • Webb B.
      • Lefebvre S.
      • Chun J.
      • Gray N.
      • Rosen H
      Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate.
      ;
      • Scott F.L.
      • Clemons B.
      • Brooks J.
      • Brahmachary E.
      • Powell R.
      • Dedman H.
      • Desale H.G.
      • Timony G.A.
      • Martinborough E.
      • Rosen H.
      • Roberts E.
      • Boehm M.F.
      • Peach R.J.
      Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity.
      ). They also target S1PR5 on oligodendrocytes and their precursors to potentially better influence remyelination (Fig. 1, Table 2) and do not require the action of phosphorylating S1P kinases for activity (
      • Liu H.
      • Sugiura M.
      • Nava V.E.
      • Edsall L.C.
      • Kono K.
      • Poulton S.
      • et al.
      Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform.
      ;
      • Kharel Y.
      • Lee S.
      • Snyder A.H.
      • Sheasley-O'neill S.L.
      • Morris M.A.
      • Setiady Y.
      • Zhu R.
      • Zigler M.A.
      • Burcin T.L.
      • Ley K.
      • Tung K.S.
      • Engelhard V.H.
      • Macdonald T.L.
      • Pearson-White S.
      • Lynch K.R
      Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720.
      ;
      • Roggeri A.
      • Schepers M.
      • Tiane A.
      • Rombaut B.
      • van Veggel L.
      • Hellings N.
      • Prickaerts J.
      • Pittaluga A.
      • Vanmierlo T.
      Sphingosine-1-phosphate receptor modulators and oligodendroglial cells: beyond immunomodulation.
      ). Although remyelination effects are largely unproven in MS, oligodendrocyte actions are unlikely to be of major importance to COVID-19, therefore targeting this pathway is unlikely to impact on SARS-CoV-2 infection or vaccination responses. However, S1PR5 modulators may affect natural killer cell function, which may influence COVID-19 biology (
      • Walzer T.
      • Chiossone L.
      • Chaix J.
      • Calver A.
      • Carozzo C.
      • Garrigue-Antar L.
      • Jacques Y.
      • Baratin M.
      • Tomasello E.
      • Vivier E.
      Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor.
      ;
      • Drouillard A.
      • Mathieu A.L.
      • Marçais A.
      • Belot A.
      • Viel S.
      • Mingueneau M.
      • Guckian K.
      • Walzer T.
      S1PR5 is essential for human natural killer cell migration toward sphingosine-1 phosphate.
      ;
      • Di Vito C.
      • Calcaterra F.
      • Coianiz N.
      • Terzoli S.
      • Voza A.
      • Mikulak J.
      • Della Bella S.
      • Mavilio D.
      Natural killer cells in SARS-CoV-2 infection: pathophysiology and therapeutic implications.
      ). However, given that the impact of these agents on natural killer cell numbers is often minimal (
      • Harris S.
      • Tran J.Q.
      • Southworth H.
      • Spencer C.M.
      • Cree B.A.C.
      • Zamvil S.S.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ) and that fingolimod, which also targets S1PR5 and is not associated with a worse prognosis following SARS-CoV-2 infection (
      • Sormani M.P.
      • Salvetti M.
      • Labauge P.
      • Schiavetti I.
      • Zephir H.
      • Carmisciano L.
      • Bensa C.
      • De Rossi N.
      • Pelletier J.
      • Cordioli C.
      • Vukusic S.
      • Moiola L.
      • Kerschen P.
      • Radaelli M.
      • Théaudin M.
      • Immovilli P.
      • Casez O.
      • Capobianco M.
      • Ciron J.
      • Trojano M.
      • Stankoff B.
      • Créange A.
      • Tedeschi G.
      • Clavelou P.
      • Comi G.
      • Thouvenot E.
      • Battaglia M.A.
      • Moreau T.
      • Patti F.
      • De Sèze J.
      • Louapre C.
      Musc-19Covisep study groups
      DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France.
      ;
      • Simpson-Yap S.
      • De Brouwer E.
      • Kalincik T.
      • Rijke N.
      • Hillert J.A.
      • Walton C.
      • Edan G.
      • Moreau Y.
      • Spelman T.
      • Geys L.
      • Parciak T.
      • Gautrais C.
      • Lazovski N.
      • Pirmani A.
      • Ardeshirdavanai A.
      • Forsberg L.
      • Glaser A.
      • McBurney R.
      • Schmidt H.
      • Bergmann A.B.
      • Braune S.
      • Stahmann A.
      • Middleton R.
      • Salter A.
      • Fox R.J.
      • van der Walt A.
      • Butzkueven H.
      • Alroughani R.
      • Ozakbas S.
      • Rojas J.I.
      • van der Mei I.
      • Nag N.
      • Ivanov R.
      • Sciascia do Olival G.
      • Dias A.E.
      • Magyari M.
      • Brum D.
      • Mendes M.F.
      • Alonso R.N.
      • Nicholas R.S.
      • Bauer J.
      • Chertcoff A.S.
      • Zabalza A.
      • Arrambide G.
      • Fidao A.
      • Comi G.
      • Peeters L.
      Associations of disease-modifying therapies with COVID-19 severity in multiple sclerosis.
      ), indicates that likewise, siponimod, ozanimod and ponesimod are unlikely to cause a worse prognosis following COVID-19 infection. Indeed, this appears to be the case in the few individuals that are reported to be infected with SARS-CoV-2 who are taking these drugs (
      • Sullivan R.
      • Kilaru A.
      • Hemmer B.
      • Cree B.A.C.
      • Greenberg B.M.
      • Kundu U.
      • Hach T.
      • DeLasHeras V.
      • Ward B.J.
      • Berger J.
      COVID-19 infection in fingolimod- or siponimod-treated patients: case series.
      ;
      • Czarnowska A.
      • Brola W.
      • Zajkowska O.
      • Rusek S.
      • Adamczyk-Sowa M.
      • Kubicka-Bączyk K.
      • Kalinowska-Łyszczarz A.
      • Kania K.
      • Słowik A.
      • Wnuk M.
      • Marona M.
      • Podlecka-Piętowska A.
      • Nojszewska M.
      • Zakrzewska-Pniewska B.
      • Jasińska E.
      • Gołuch K.
      • Lech B.
      • Noga M.
      • Perenc A.
      • Popiel M.
      • Lasek-Bal A.
      • Puz P.
      • Maciejowska K.
      • Kucharska-Lipowska M.
      • Lipowski M.
      • Kapica-Topczewska K.
      • Chorąży M.
      • Tarasiuk J.
      • Kochanowicz J.
      • Kulikowska J.
      • Wawrzyniak S.
      • Niezgodzińska-Maciejek A.
      • Pokryszko-Dragan A.
      • Gruszka E.
      • Budrewicz S.
      • Białek M.
      • Kurkowska-Jastrzębska I.
      • Kurowska K.
      • Stępień A.
      • Włodek A.
      • Ptasznik V.
      • Pawełczyk M.
      • Sobolewski P.
      • Lejmel H.
      • Strzalińska K.
      • Maciejowski M.
      • Tutaj A.
      • Zwiernik J.
      • Litwin A.
      • Lewańczyk B.
      • Paprocka I.
      • Zwiernik B.
      • Pawlos A.
      • Borysowicz A.
      • Narożnik A.
      • Michałowska A.
      • Nosek K.
      • Fudala M.
      • Milewska-Jędrzejczak M.
      • Kułakowska A.
      • Bartosik-Psujek H.
      Clinical course and outcome of SARS-CoV-2 infection in multiple sclerosis patients treated with disease-modifying therapies - the Polish experience.
      ;
      • Berger J.
      • Sullivan R.
      • Kilaru A.
      • Hemmer B.
      • Cree B.A.C.
      • Greenberg B.M.
      • DeLasHeras V.
      • Ward B.J.
      COVID-19 outcomes in fingolimod- or siponimod-treated patients: clinical trial and post marketing cases P726.
      ,

      Cree B.A., Selmaj K.W., Steinman L., Comi G., Bar-Or A., Arnold D.L., Hartung H.P., Montal X., Havrdova E.K., Desai H., Sheffield J.K., Minton N., Cheng C.Y., Silva D., Kappos L., Cohen J.A. COVID-19 infections and vaccinations among patients receiving ozanimod in the daybreak open-label extension study P387. Mult. Scler. 2022*, 28 (3S):401–402.

      ). Natural killer cells are unlikely to exhibit a major effect on the generation of T and B cell responses and this suggests that siponimod, ozanimod and ponesimod may behave similarly regarding vaccination.

      4.1 Sphingosine-1-phopshate receptors controlling multiple sclerosis and COVID-19 infection and vaccine responses

      Currently all approved S1PR modulators target S1P1R (Table 2). These may be agonists that trigger receptor internalisation and degradation (S1PR1) or internalization and recycling (S1PR3 and S1PR4) to be functional antagonists at S1PR1, S1PR3, S1PR4 and possibly agonists at S1PR5, which appears not to internalize (
      • Grassi S.
      • Mauri L.
      • Prioni S.
      • Cabitta L.
      • Sonnino S.
      • Prinetti A.
      • Giussani P.
      Sphingosine 1-phosphate receptors and metabolic enzymes as druggable targets for brain diseases.
      ;
      • Cyster J.G.
      • Schwab S.R.
      Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.
      ;
      • Bigaud M.
      • Nuesslein-Hildesheim B.
      • Tran T.T.T.
      • Guerini D.
      Siponimod and fingolimod down regulate S1P1 but no effect on S1P5.
      ). Simplistically, S1PR1 is involved in lymphocyte egress from bone-marrow and some lymphoid tissues and therefore S1P1R modulators are associated with a rapid peripheral lymphopenia limiting entry of pathogenic cells into the CNS (
      • Mehling M.
      • Brinkmann V.
      • Antel J.
      • Bar-Or A.
      • Goebels N.
      • Vedrine C.
      • Kristofic C.
      • Kuhle J.
      • Lindberg R.L.
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ;
      • Jurcevic S.
      • Juif P.E.
      • Hamid C.
      • Greenlaw R.
      • D'Ambrosio D.
      • Dingemanse J
      Effects of multiple-dose ponesimod, a selective S1P1 receptor modulator, on lymphocyte subsets in healthy humans.
      ;
      • Harris S.
      • Tran J.Q.
      • Southworth H.
      • Spencer C.M.
      • Cree B.A.C.
      • Zamvil S.S.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ;
      • Cyster J.G.
      • Schwab S.R.
      Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.
      ;
      • Brossard P.
      • Derendorf H.
      • Xu J.
      • Maatouk H.
      • Halabi A.
      • Dingemanse J.
      Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study.
      ;
      • Mandala S.
      • Hajdu R.
      • Bergstrom J.
      • Quackenbush E.
      • Xie J.
      • Milligan J.
      • Thornton R.
      • Shei G.J.
      • Card D.
      • Keohane C.
      • Rosenbach M.
      • Hale J.
      • Lynch C.L.
      • Rupprecht K.
      • Parsons W.
      • Rosen H.
      Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
      ;
      • Matloubian M.
      • Lo C.G.
      • Cinamon G.
      • Lesneski M.J.
      • Xu Y.
      • Brinkmann V.
      • Allende M.L.
      • Proia R.L.
      • Cyster J.G.
      Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.
      ). In addition, S1PR1 is also expressed by the vascular system and brain endothelial cells, hence S1PR modulation can further inhibit leucocyte trafficking into the CNS to prevent disease (
      • Zhao Y.
      • Shi D.
      • Cao K.
      • Wu F.
      • Zhu X.
      • Wen S.
      • You Q.
      • Zhang K.
      • Liu L.
      • Zhou H.
      Fingolimod targets cerebral endothelial activation to block leukocyte recruitment in the central nervous system.
      ;
      • Spampinato S.F.
      • Obermeier B.
      • Cotleur A.
      • Love A.
      • Takeshita Y.
      • Sano Y.
      • Kanda T.
      • Ransohoff R.M.
      Sphingosine 1 phosphate at the blood brain barrier: can the modulation of S1P receptor 1 influence the response of endothelial cells and astrocytes to inflammatory stimuli?.
      ). This may be further influenced by astrocytic S1PR1/S1PR3 activity, as astrocytes are known to be involved in blood-brain barrier formation and targeting astrocytes probably serves to help inhibit disease (
      • Choi J.W.
      • Gardell S.E.
      • Herr D.R.
      • Rivera R.
      • Lee C.W.
      • Noguchi K.
      • Teo S.T.
      • Yung Y.C.
      • Lu M.
      • Kennedy G.
      • Chun J.
      FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation.
      ;
      • van Doorn R.
      • Nijland P.G.
      • Dekker N.
      • Witte M.E.
      • Lopes-Pinheiro M.A.
      • van het Hof B.
      • Kooij G.
      • Reijerkerk A.
      • Dijkstra C.
      • van van der Valk P.
      • van Horssen J.
      • de Vries H.E.
      Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes.
      ;
      • Spampinato S.F.
      • Merlo S.
      • Costantino G.
      • Sano Y.
      • Kanda T.
      • Sortino M.A.
      Decreased astrocytic CCL2 accounts for BAF-312 effect on pbmcs transendothelial migration through a blood brain barrier in vitro model.
      ).
      Although it is clear that CD4, CD8 and CD19 expressing T and B lymphocytes are markedly inhibited following S1P1R internalization, it is evident that there is differential inhibition of lymphocyte subsets notably due to S1PR1 and CCR7 chemokine receptors (
      • Mehling M.
      • Brinkmann V.
      • Antel J.
      • Bar-Or A.
      • Goebels N.
      • Vedrine C.
      • Kristofic C.
      • Kuhle J.
      • Lindberg R.L.
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ;
      • Jurcevic S.
      • Juif P.E.
      • Hamid C.
      • Greenlaw R.
      • D'Ambrosio D.
      • Dingemanse J
      Effects of multiple-dose ponesimod, a selective S1P1 receptor modulator, on lymphocyte subsets in healthy humans.
      ;
      • Harris S.
      • Tran J.Q.
      • Southworth H.
      • Spencer C.M.
      • Cree B.A.C.
      • Zamvil S.S.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ;
      • Lu E.
      • Cyster J.G.
      G-protein coupled receptors and ligands that organize humoral immune responses.
      ;
      • Hjorth M.
      • Dandu N.
      • Mellergård J.
      Treatment effects of fingolimod in multiple sclerosis: selective changes in peripheral blood lymphocyte subsets.
      ). This indicates that many studies showing diminished T cell responsiveness against SARS-CoV-2 vaccination are not measuring the same populations of T cells, which may have different stimulation thresholds and cytokine release profiles (
      • Sallusto F.
      • Lenig D.
      • Förster R.
      • Lipp M.
      • Lanzavecchia A.
      Two subsets of memory T ymphocytes with distinct homing potentials and effector functions.
      ;
      • Geginat J.
      • Lanzavecchia A.
      • Sallusto F.
      Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines.
      ). As such naïve (CD45RA+, CCR7+) and central memory [CD45RO+, CCR7+) populations, which are the cells that will generate new responses in lymph nodes are trapped and maintained in lymphoid tissues and bone marrow (
      • Mehling M.
      • Brinkmann V.
      • Antel J.
      • Bar-Or A.
      • Goebels N.
      • Vedrine C.
      • Kristofic C.
      • Kuhle J.
      • Lindberg R.L.
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ;
      • Hjorth M.
      • Dandu N.
      • Mellergård J.
      Treatment effects of fingolimod in multiple sclerosis: selective changes in peripheral blood lymphocyte subsets.
      ). The effector memory (CD45RO+, CCR7+) and notably effector T-cells (CD45RA+, CCR7-), which will give the protective anti-viral responses in tissues can enter the circulation to promote defence against pathogens (
      • Mehling M.
      • Brinkmann V.
      • Antel J.
      • Bar-Or A.
      • Goebels N.
      • Vedrine C.
      • Kristofic C.
      • Kuhle J.
      • Lindberg R.L.
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ;
      • Jurcevic S.
      • Juif P.E.
      • Hamid C.
      • Greenlaw R.
      • D'Ambrosio D.
      • Dingemanse J
      Effects of multiple-dose ponesimod, a selective S1P1 receptor modulator, on lymphocyte subsets in healthy humans.
      ;
      • Harris S.
      • Tran J.Q.
      • Southworth H.
      • Spencer C.M.
      • Cree B.A.C.
      • Zamvil S.S.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ;
      • Hjorth M.
      • Dandu N.
      • Mellergård J.
      Treatment effects of fingolimod in multiple sclerosis: selective changes in peripheral blood lymphocyte subsets.
      ). Furthermore, as lymphoid tissue retention of CD8+ T-cell is less marked than seen with CD4+ T cells, peripheral effector CD8+ T-cells are enriched (
      • Mehling M.
      • Brinkmann V.
      • Antel J.
      • Bar-Or A.
      • Goebels N.
      • Vedrine C.
      • Kristofic C.
      • Kuhle J.
      • Lindberg R.L.
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ;
      • Jurcevic S.
      • Juif P.E.
      • Hamid C.
      • Greenlaw R.
      • D'Ambrosio D.
      • Dingemanse J
      Effects of multiple-dose ponesimod, a selective S1P1 receptor modulator, on lymphocyte subsets in healthy humans.
      ;
      • Hjorth M.
      • Dandu N.
      • Mellergård J.
      Treatment effects of fingolimod in multiple sclerosis: selective changes in peripheral blood lymphocyte subsets.
      ;
      • Johnson T.A.
      • Lapierre Y.
      • Bar-Or A.
      • Antel J.P.
      Distinct properties of circulating CD8+ T cells in FTY720-treated patients with multiple sclerosis.
      ). This will further aid anti-viral immune responses that promote recovery from COVID-19. However, this is a relative escape and there is an absolute reduction in effector memory cells, which are the major T-cell subset entering the CNS during MS (
      • Hjorth M.
      • Dandu N.
      • Mellergård J.
      Treatment effects of fingolimod in multiple sclerosis: selective changes in peripheral blood lymphocyte subsets.
      ;
      • Mullen K.M.
      • Gocke A.R.
      • Allie R.
      • Ntranos A.
      • Grishkan I.V.
      • Pardo C.
      • Calabresi P.A
      Expression of CCR7 and CD45RA in CD4+ and CD8+ subsets in cerebrospinal fluid of 134 patients with inflammatory and non-inflammatory neurological diseases.
      ). Thus, this action could promote efficacy in MS, in addition to any effect on central memory T cells (
      • Song Z.Y.
      • Yamasaki R.
      • Kawano Y.
      • Sato S.
      • Masaki K.
      • Yoshimura S.
      • Matsuse D.
      • Murai H.
      • Matsushita T.
      • Kira J.
      Peripheral blood T cell dynamics predict relapse in multiple sclerosis patients on fingolimod.
      ).
      Furthermore, the peripheral memory B cells are a major subsets of B cells implicated in MS pathogenesis and are affected along with naïve B cells, at least for fingolimod (
      • Baker D.
      • Marta M.
      • Pryce G.
      • Giovannoni G.
      • Schmierer K
      Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis.
      ;
      • Johansson D.
      • Rauld C.
      • Roux J.
      • Regairaz C.
      • Galli E.
      • Callegari I.
      • Raad L.
      • Waldt A.
      • Cuttat R.
      • Roma G.
      • Diebold M.
      • Becher B.
      • Kuhle J.
      • Derfuss T.
      • Carballido J.M.
      • Sanderson N.S.R.
      Mass cytometry of CSF identifies an MS-associated B-cell population.
      ;
      • Kemmerer C.L.
      • Pernpeintner V.
      • Ruschil C.
      • Abdelhak A.
      • Scholl M.
      • Ziemann U.
      • Krumbholz M.
      • Hemmer B.
      • Kowarik M.C.
      Differential effects of disease modifying drugs on peripheral blood B cell subsets: a cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab.
      ;
      • Kowarik M.C.
      • Astling D.
      • Lepennetier G.
      • Ritchie A.
      • Hemmer B.
      • Owens G.P.
      • Bennett J.L.
      Differential effects of Fingolimod and natalizumab on B cell repertoires in multiple sclerosis patients.
      ). Importantly, fingolimod, like most other MS-disease modifying treatments, targets the adaptive immune response and does not induce marked changes to the peripheral innate immune response, which are sentinels located within the affected tissues and appear to be central to SARS-CoV-2 removal (
      • Baker D.
      • Amor S.
      • Kang A.S.
      • Schmierer K.
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ;
      • Kemmerer C.L.
      • Pernpeintner V.
      • Ruschil C.
      • Abdelhak A.
      • Scholl M.
      • Ziemann U.
      • Krumbholz M.
      • Hemmer B.
      • Kowarik M.C.
      Differential effects of disease modifying drugs on peripheral blood B cell subsets: a cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab.
      ;
      • Amor S.
      • Fernández Blanco L.
      • Baker D
      Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage.
      ). This is facilitated by the cytotoxic T cell response and the subsequent generation of cytopathic and neutralizing antibodies that can help protect against re-infection (
      • Baker D.
      • Amor S.
      • Kang A.S.
      • Schmierer K.
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ;
      • Baker D.
      • Roberts C.A.K.
      • Pryce G.
      • Kang A.S.
      • Marta M.
      • Reyes S.
      • Schmierer K.
      • Giovannoni G.
      • Amor S
      COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.
      ;
      • Sormani M.P.
      • Schiavetti I.
      • Inglese M.
      • Carmisciano L.
      • Laroni A.
      • Lapucci C.
      • Visconti V.
      • Serrati C.
      • Gandoglia I.
      • Tassinari T.
      • Perego G.
      • Brichetto G.
      • Gazzola P.
      • Mannironi A.
      • Stromillo M.L.
      • Cordioli C.
      • Landi D.
      • Clerico M.
      • Signoriello E.
      • Cocco E.
      • Frau J.
      • Ferrò M.T.
      • Di Sapio A.
      • Pasquali L.
      • Ulivelli M.
      • Marinelli F.
      • Pizzorno M.
      • Callari G.
      • Iodice R.
      • Liberatore G.
      • Caleri F.
      • Repice A.M.
      • Cordera S.
      • Battaglia M.A.
      • Salvetti M.
      • Franciotta D.
      • Uccelli A.
      CovaXiMS study group
      Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.
      ). Antibody responses can be generated within the lymphoid tissue from immature and naïve B cells, which seem to express many S1PR (Fig. 2) and thus may not require re-circulation to tissues to induce antibody-producing plasma cells that could facilitate removal of the SARS-CoV-2 virus (
      • Turner J.S.
      • O'Halloran J.A.
      • Kalaidina E.
      • Kim W.
      • Schmitz A.J.
      • Zhou J.Q.
      • Lei T.
      • Thapa M.
      • Chen R.E.
      • Case J.B.
      • Amanat F.
      • Rauseo A.M.
      • Haile A.
      • Xie X.
      • Klebert M.K.
      • Suessen T.
      • Middleton W.D.
      • Shi P.Y.
      • Krammer F.
      • Teefey S.A.
      • Diamond M.S.
      • Presti R.M.
      • Ellebedy A.H.
      SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses.
      ;
      • Kim W.
      • Zhou J.Q.
      • Horvath S.C.
      • Schmitz A.J.
      • Sturtz A.J.
      • Lei T.
      • Liu Z.
      • Kalaidina E.
      • Thapa M.
      • Alsoussi W.B.
      • Haile A.
      • Klebert M.K.
      • Suessen T.
      • Parra-Rodriguez L.
      • Mudd P.A.
      • Whelan S.P.J.
      • Middleton W.D.
      • Teefey S.A.
      • Pusic I.
      • O'Halloran J.A.
      • Presti R.M.
      • Turner J.S.
      • Ellebedy A.H
      Germinal centre-driven maturation of B cell response to mRNA vaccination.
      ). However, S1P1R is involved in the release of immature B cells from bone marrow and B cell migration within lymphoid tissues that involves shuttling of B cells from marginal zones and B cell follicles using S1PR1 and CXCR5, responding to CXCL13 (
      • Lu E.
      • Cyster J.G.
      G-protein coupled receptors and ligands that organize humoral immune responses.
      ;
      • Cinamon G.
      • Zachariah M.A.
      • Lam O.M.
      • Foss Jr, F.W.
      • Cyster J.G.
      Follicular shuttling of marginal zone B cells facilitates antigen transport.
      ;
      • Allende M.L.
      • Tuymetova G.
      • Lee B.G.
      • Bonifacino E.
      • Wu Y.P.
      • Proia R.L.
      S1P1 receptor directs the release of immature B cells from bone marrow into blood.
      ). This could contribute to the reduction of SARS-CoV-2 B cell responses as seen with fingolimod (
      • Wu X.
      • Wang L.
      • Shen L.
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis.
      ;
      • Gombolay G.Y.
      • Dutt M.
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ).
      Fig. 2
      Fig. 2Sphinogsine-1-phosphate receptor distribution in human and mouse cells. The S1PR mRNA expression distributions from cells and tissues were extracted from Affimetrix RNAseq data in the human Primary Cell Atlas or the mouse GeneAtlas MOE430 gcrma datasets at www.biogps.org, using the indicated S1PR-specific probes. The results represent the mean ± standard error of the mean expression of 2–21 individual samples of normalised expression data. Human macrophages and dendritic cells were monocyte-derived and the monocytes expressing S1PR3 were from the CD14+ subset (935±55a.u.) compared to the CD16+ (76±55a.u. n = 3). a.u. arbitrary units. The human natural killer cells subset examined, expressed CD56, CD62 antigens.
      Vaccine responses during fingolimod treatment are blunted compared to untreated individuals with a seroconversion rate of 60.2% in a meta-analysis of n = 785 people treated with S1PR modulators, largely taking fingolimod n = 764 (
      • Wu X.
      • Wang L.
      • Shen L.
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis.
      ). This was supported in an additional meta-analysis examining only fingolimod treatment, which reported an antibody response in n = 160/220 (72.7%) vaccinated and n = 152/198 (76.8%) mRNA-vaccinated, fingolimod-treated individuals (Table 3) (
      • Gombolay G.Y.
      • Dutt M.
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ). In addition other S1PR modulators also exhibited a blunted vaccine response, seen as reduced antibody titres compared to untreated individuals following SARS-CoV-2 treated vaccination in animals or people with MS treated with either: siponimod (n = 50) (
      • Ziemssen T.
      • Groth M.
      • Rauser B.
      • Bopp T.
      Assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod-treated patients: a nonrandomized controlled clinical trial (AMA-VACC).
      ,
      • Siddiqui G.
      • Maloni H.
      • Nava V.E.
      Adequate antibody response to BioNTech COVID vaccine in a multiple sclerosis patient treated with siponimod.
      ;
      • Krbot Skorić M.
      • Rogić D.
      • Lapić I.
      • Šegulja D.
      • Habek M
      Humoral immune response to COVID-19 vaccines in people with secondary progressive multiple sclerosis treated with siponimod.
      ;
      • Milo R.
      • Staun-Ram E.
      • Karussis D.
      • Karni A.
      • Hellmann M.A.
      • Bar-Haim E.
      • Miller A.
      Israeli Neuroimmunology study group on COVID-19 vaccination in multiple sclerosis
      Humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis: an Israeli multi-center experience following 3 vaccine doses.
      ;
      • Satyanarayan S.
      • Safi N.
      • Sorets T.
      • Filomena S.
      • Zhang Y.
      • Klineova S.
      • Fabian M.
      • Horng S.
      • Tankou S.
      • Miller A.
      • Krieger S.
      • Lublin F.
      • Sumowski J.
      • Katz Sand I.
      ;
      • Bar-Or A.
      • Mao-Draayer Y.
      • Delgado S.R.
      • Fox R.J.
      • Cruz L.A.
      • Meng X.
      Mavrikis Cox G5
      Evaluating humoral immune response to mRNA COVID-19 vaccines in siponimod-treated patients with advancing forms of relapsing multiple sclerosis: a COVID-19 vaccine sub-study of phase 3b EXCHANGE trial.
      ), ozanimod (n = 228) (
      • Satyanarayan S.
      • Safi N.
      • Sorets T.
      • Filomena S.
      • Zhang Y.
      • Klineova S.
      • Fabian M.
      • Horng S.
      • Tankou S.
      • Miller A.
      • Krieger S.
      • Lublin F.
      • Sumowski J.
      • Katz Sand I.
      ;
      • Kantor D.
      SARS-CoV-2 vaccine response in RMS patients treated with ozanimod and other DMTs P13-4.008.
      ,
      • Cree B.A.C.
      • Maddux R.
      • Bar-Or A.
      • Hartung H.P.
      • Kaur A.
      • Brown E.
      • Hu S.
      • Sheffield J.K.
      • Silva D.
      • Harris S.
      Serologic response and clinical outcomes of sars-cov-2 infection and vaccination in ozanimod-treated participants with relapsing multiple sclerosis.
      ,
      • Akgün K.
      • Dunsche M.
      • Katoul Al Rahbani G.
      • Woopen C.
      • Ziemssen T
      Different type and timing of S1P receptor modulator therapy impacts T and B cell response after SARS-CoV2 vaccination P316.
      ) or ponesimod (n = 103) (
      • Spiller K.
      • Aras R.
      • DeGuzman M.
      • Ramsburg E.
      • Bhattacharya A.
      A short pause in ponesimod treatment completely restores the ability to mount post-vaccination antibody titers in mice P646.
      ,
      • Wong J.
      • Hertoghs N.
      • Lemle A.
      • Linscheid P.
      • Raghavan N.
      • Singh A.
      • Sidorenko T..
      COVID-19 antibody response by vaccine type and lymphocyte count in RMS patients on ponesimod: results from Phase 2 long-term extension study AC-058B202.
      ) (Table 3). This suggests an important impact of S1PR1 on vaccine-induced antibody responses.
      Table 3Influence of S1PR modulation on SARS-CoV-2 vaccine responses.
      S1PR modulatorNo. seroconversion/Total

      (% response) & subgroup
      SARS-CoV-2 Assay

      (Source)
      T cell Response assessedReference
      Fingolimod160/220 (72.7%) VariedMultipleYes
      • Gombolay G.Y.
      • Dutt M.
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      152/198 (76.8%) mRNA
      20/37 (54.1%) mRNAECLIA (Abbott)Yes
      • Milo R.
      • Staun-Ram E.
      • Karussis D.
      • Karni A.
      • Hellmann M.A.
      • Bar-Haim E.
      • Miller A.
      Israeli Neuroimmunology study group on COVID-19 vaccination in multiple sclerosis
      Humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis: an Israeli multi-center experience following 3 vaccine doses.
      11/18 (61.1%) VariedMultipleNo
      • Satyanarayan S.
      • Safi N.
      • Sorets T.
      • Filomena S.
      • Zhang Y.
      • Klineova S.
      • Fabian M.
      • Horng S.
      • Tankou S.
      • Miller A.
      • Krieger S.
      • Lublin F.
      • Sumowski J.
      • Katz Sand I.
      n = 86 (27.9%) mRNACLIA (DiaSorin)Yes
      • Akgün K.
      • Dunsche M.
      • Katoul Al Rahbani G.
      • Woopen C.
      • Ziemssen T
      Different type and timing of S1P receptor modulator therapy impacts T and B cell response after SARS-CoV2 vaccination P316.
      Indicates that the public domain information may not have been peer-reviewed.
      Siponimod15/21 (71.4%) mRNANeutralization assayYes
      • Ziemssen T.
      • Groth M.
      • Rauser B.
      • Bopp T.
      Assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod-treated patients: a nonrandomized controlled clinical trial (AMA-VACC).
      Indicates that the public domain information may not have been peer-reviewed.
      1/1 (100%) mRNAECLIA (Roche)No
      • Siddiqui G.
      • Maloni H.
      • Nava V.E.
      Adequate antibody response to BioNTech COVID vaccine in a multiple sclerosis patient treated with siponimod.
      11/13 (84.6%) VariedECLIA (Roche)No
      • Krbot Skorić M.
      • Rogić D.
      • Lapić I.
      • Šegulja D.
      • Habek M
      Humoral immune response to COVID-19 vaccines in people with secondary progressive multiple sclerosis treated with siponimod.
      3/3 (100%) mRNAECLIA (Abbott)No
      • Milo R.
      • Staun-Ram E.
      • Karussis D.
      • Karni A.
      • Hellmann M.A.
      • Bar-Haim E.
      • Miller A.
      Israeli Neuroimmunology study group on COVID-19 vaccination in multiple sclerosis
      Humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis: an Israeli multi-center experience following 3 vaccine doses.
      7/8 (87.5%) VariedMultipleNo
      • Satyanarayan S.
      • Safi N.
      • Sorets T.
      • Filomena S.
      • Zhang Y.
      • Klineova S.
      • Fabian M.
      • Horng S.
      • Tankou S.
      • Miller A.
      • Krieger S.
      • Lublin F.
      • Sumowski J.
      • Katz Sand I.
      4/5 (80.0%) mRNASARS-CoV IgGNo
      • Bar-Or A.
      • Mao-Draayer Y.
      • Delgado S.R.
      • Fox R.J.
      • Cruz L.A.
      • Meng X.
      Mavrikis Cox G5
      Evaluating humoral immune response to mRNA COVID-19 vaccines in siponimod-treated patients with advancing forms of relapsing multiple sclerosis: a COVID-19 vaccine sub-study of phase 3b EXCHANGE trial.
      Indicates that the public domain information may not have been peer-reviewed.
      Ozanimod3/3 (100%) VariedMultipleNo
      • Satyanarayan S.
      • Safi N.
      • Sorets T.
      • Filomena S.
      • Zhang Y.
      • Klineova S.
      • Fabian M.
      • Horng S.
      • Tankou S.
      • Miller A.
      • Krieger S.
      • Lublin F.
      • Sumowski J.
      • Katz Sand I.
      30/30 (100%) VariedECLIA (Roche)Yes
      • Kantor D.
      SARS-CoV-2 vaccine response in RMS patients treated with ozanimod and other DMTs P13-4.008.
      Indicates that the public domain information may not have been peer-reviewed.
      137/148 (92.6%) VariedECLIA (Roche)No
      • Cree B.A.C.
      • Maddux R.
      • Bar-Or A.
      • Hartung H.P.
      • Kaur A.
      • Brown E.
      • Hu S.
      • Sheffield J.K.
      • Silva D.
      • Harris S.
      Serologic response and clinical outcomes of sars-cov-2 infection and vaccination in ozanimod-treated participants with relapsing multiple sclerosis.
      Indicates that the public domain information may not have been peer-reviewed.
      39/39 (100%) Exposed
      98/109 (89.9%) Naïve
      80/80 (100%) mRNA
      n = 47 (84.2%) mRNACLIA (DiaSorin)Yes
      • Akgün K.
      • Dunsche M.
      • Katoul Al Rahbani G.
      • Woopen C.
      • Ziemssen T
      Different type and timing of S1P receptor modulator therapy impacts T and B cell response after SARS-CoV2 vaccination P316.
      Indicates that the public domain information may not have been peer-reviewed.
      Ponesimod89/103 (86.4%) VariedELISA (Nexelis)No
      • Wong J.
      • Hertoghs N.
      • Lemle A.
      • Linscheid P.
      • Raghavan N.
      • Singh A.
      • Sidorenko T..
      COVID-19 antibody response by vaccine type and lymphocyte count in RMS patients on ponesimod: results from Phase 2 long-term extension study AC-058B202.
      Indicates that the public domain information may not have been peer-reviewed.
      11/11 (100%) Exposed
      33/38 (86.8%) Naïve
      29/32 (90.6%) mRNA
      Information was extracted from data tables from a meta-analysis of 31 studies on the influence fingolimod treatment on SARS-CoV-2 vaccination (two doses). This was contrasted with individual public domain studies of SARS-CoV-2 vaccination in people treated with either siponimod, ozanimod or ponesimod. The results show the number of serological responders, defined within their studies, from the total analysed in response to any Index SARS-CoV-2 vaccine (varied) or stratified into those receiving only mRNA vaccines. Data was also stratified into those potentially previously exposed to COVID-19 infection, indicated by serological responses to SARS-CoV-2 nucleocapsid, or were considered to be infection-naïve in the absence of nucleocapsid serology. Where defined the SARS-Cov-2, antibody detection assay and manufacturer was indicated and these included electro-chemiluminescent immunoassay (ECLIA) and enzyme-linked immunosorbent assays (ELISA). It is indicated whether SARS-CoV-2 T-cell recall responses were performed. The source references are indicated.
      low asterisk Indicates that the public domain information may not have been peer-reviewed.
      Interestingly, although the numbers of studies on non-fingolimod, S1PR modulators are relatively small and the differences observed may be part of the variability between studies, including the nature of the vaccines and the immune-response detection assays used, it seems that there are better seroconversion rates seen in the majority of people treated with siponimod, ozanimod and ponesimod (Table 3). This contrasts with studies on fingolimod that often report that the minority of people seroconvert following vaccination (
      • Wu X.
      • Wang L.
      • Shen L.
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis.
      ;
      • Gombolay G.Y.
      • Dutt M.
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ;
      • Ziemssen T.
      • Groth M.
      • Rauser B.
      • Bopp T.
      Assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod-treated patients: a nonrandomized controlled clinical trial (AMA-VACC).
      ,
      • Siddiqui G.
      • Maloni H.
      • Nava V.E.
      Adequate antibody response to BioNTech COVID vaccine in a multiple sclerosis patient treated with siponimod.
      ;
      • Krbot Skorić M.
      • Rogić D.
      • Lapić I.
      • Šegulja D.
      • Habek M
      Humoral immune response to COVID-19 vaccines in people with secondary progressive multiple sclerosis treated with siponimod.
      ;
      • Milo R.
      • Staun-Ram E.
      • Karussis D.
      • Karni A.
      • Hellmann M.A.
      • Bar-Haim E.
      • Miller A.
      Israeli Neuroimmunology study group on COVID-19 vaccination in multiple sclerosis
      Humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis: an Israeli multi-center experience following 3 vaccine doses.
      ;
      • Satyanarayan S.
      • Safi N.
      • Sorets T.
      • Filomena S.
      • Zhang Y.
      • Klineova S.
      • Fabian M.
      • Horng S.
      • Tankou S.
      • Miller A.
      • Krieger S.
      • Lublin F.
      • Sumowski J.
      • Katz Sand I.
      ;
      • Bar-Or A.
      • Mao-Draayer Y.
      • Delgado S.R.
      • Fox R.J.
      • Cruz L.A.
      • Meng X.
      Mavrikis Cox G5
      Evaluating humoral immune response to mRNA COVID-19 vaccines in siponimod-treated patients with advancing forms of relapsing multiple sclerosis: a COVID-19 vaccine sub-study of phase 3b EXCHANGE trial.
      ;
      • Kantor D.
      SARS-CoV-2 vaccine response in RMS patients treated with ozanimod and other DMTs P13-4.008.
      ,
      • Cree B.A.C.
      • Maddux R.
      • Bar-Or A.
      • Hartung H.P.
      • Kaur A.
      • Brown E.
      • Hu S.
      • Sheffield J.K.
      • Silva D.
      • Harris S.
      Serologic response and clinical outcomes of sars-cov-2 infection and vaccination in ozanimod-treated participants with relapsing multiple sclerosis.
      ,
      • Akgün K.
      • Dunsche M.
      • Katoul Al Rahbani G.
      • Woopen C.
      • Ziemssen T
      Different type and timing of S1P receptor modulator therapy impacts T and B cell response after SARS-CoV2 vaccination P316.
      ,
      • Wong J.
      • Hertoghs N.
      • Lemle A.
      • Linscheid P.
      • Raghavan N.
      • Singh A.
      • Sidorenko T..
      COVID-19 antibody response by vaccine type and lymphocyte count in RMS patients on ponesimod: results from Phase 2 long-term extension study AC-058B202.
      ). This could suggest that S1PR3 and S1PR4, which are widely expressed by the immune system (Fig. 2), contribute to lower antibody titres following vaccination, as suggested by the underlying biology.
      Consistent with other studies (
      • Khoury D.S.
      • Cromer D.
      • Reynaldi A.
      • Schlub T.E.
      • Wheatley A.K.
      • Juno J.A.
      • Subbarao K.
      • Kent S.J.
      • Triccas J.A.
      • Davenport M.P.
      Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.
      ), the level of seroconversion is influenced by the nature of administered vaccine (Table 3) (
      • Khoury D.S.
      • Cromer D.
      • Reynaldi A.
      • Schlub T.E.
      • Wheatley A.K.
      • Juno J.A.
      • Subbarao K.
      • Kent S.J.
      • Triccas J.A.
      • Davenport M.P.
      Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.
      ). As such, mRNA vaccines induce better seroconversion than seen following viral vector use (
      • Wu X.
      • Wang L.
      • Shen L.
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis.
      ;
      • Gombolay G.Y.
      • Dutt M.
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ;
      • Tallantyre E.C.
      • Vickaryous N.
      • Anderson V.
      • Asardag A.N.
      • Baker D.
      • Bestwick J.
      • Bramhall K.
      • Chance R.
      • Evangelou N.
      • George K.
      • Giovannoni G.
      • Godkin A.
      • Grant L.
      • Harding K.E.
      • Hibbert A.
      • Ingram G.
      • Jones M.
      • Kang A.S.
      • Loveless S.
      • Moat S.J.
      • Robertson N.P.
      • Schmierer K.
      • Scurr M.J.
      • Shah S.N.
      • Simmons J.
      • Upcott M.
      • Willis M.
      • Jolles S.
      • Dobson R.
      COVID-19 vaccine response in people with multiple sclerosis.
      ). Meta-analysis indicates responses in n = 152/198 (76.8%) mRNA vaccinated individuals vs. n = 8/22 (36.4%) individuals vaccinated with SARS-CoV-2 viral vectors administered during fingolimod (
      • Wu X.
      • Wang L.
      • Shen L.
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis.
      ) and was seen with ozanimod and ponesimod (Table 3) (
      • Cree B.A.C.
      • Maddux R.
      • Bar-Or A.
      • Hartung H.P.
      • Kaur A.
      • Brown E.
      • Hu S.
      • Sheffield J.K.
      • Silva D.
      • Harris S.
      Serologic response and clinical outcomes of sars-cov-2 infection and vaccination in ozanimod-treated participants with relapsing multiple sclerosis.
      ,
      • Wong J.
      • Hertoghs N.
      • Lemle A.
      • Linscheid P.
      • Raghavan N.
      • Singh A.
      • Sidorenko T..
      COVID-19 antibody response by vaccine type and lymphocyte count in RMS patients on ponesimod: results from Phase 2 long-term extension study AC-058B202.
      ). Likewise, as anticipated there were more marked vaccine responses in people who have seroconverted following natural SARS-CoV-2 infection (Table 3) (
      • Cree B.A.C.
      • Maddux R.
      • Bar-Or A.
      • Hartung H.P.
      • Kaur A.
      • Brown E.
      • Hu S.
      • Sheffield J.K.
      • Silva D.
      • Harris S.
      Serologic response and clinical outcomes of sars-cov-2 infection and vaccination in ozanimod-treated participants with relapsing multiple sclerosis.
      ,
      • Wong J.
      • Hertoghs N.
      • Lemle A.
      • Linscheid P.
      • Raghavan N.
      • Singh A.
      • Sidorenko T..
      COVID-19 antibody response by vaccine type and lymphocyte count in RMS patients on ponesimod: results from Phase 2 long-term extension study AC-058B202.
      ). Therefore, the demographics of individuals vaccinated will potentially influence study outcome.
      Furthermore, it could also be argued that the possible subtle differences reported between fingolimod and the more recently approved variants may relate to biology created by the changing circulating SARS-CoV-2 variants of concern and thresholds of immunity required for immune protection (
      • Sormani M.P.
      • Schiavetti I.
      • Inglese M.
      • Carmisciano L.
      • Laroni A.
      • Lapucci C.
      • Visconti V.
      • Serrati C.
      • Gandoglia I.
      • Tassinari T.
      • Perego G.
      • Brichetto G.
      • Gazzola P.
      • Mannironi A.
      • Stromillo M.L.
      • Cordioli C.
      • Landi D.
      • Clerico M.
      • Signoriello E.
      • Cocco E.
      • Frau J.
      • Ferrò M.T.
      • Di Sapio A.
      • Pasquali L.
      • Ulivelli M.
      • Marinelli F.
      • Pizzorno M.
      • Callari G.
      • Iodice R.
      • Liberatore G.
      • Caleri F.
      • Repice A.M.
      • Cordera S.
      • Battaglia M.A.
      • Salvetti M.
      • Franciotta D.
      • Uccelli A.
      CovaXiMS study group
      Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.
      ;
      • Ohashi H.
      • Hishiki T.
      • Akazawa D.
      • Kim K.S.
      • Woo J.
      • Shionoya K.
      • Tsuchimoto K.
      • Iwanami S.
      • Moriyama S.
      • Kinoshita H.
      • Yamada S.
      • Kuroda Y.
      • Yamamoto T.
      • Kishida N.
      • Watanabe S.
      • Hasegawa H.
      • Ebihara H.
      • Suzuki T.
      • Maeda K.
      • Fukushi S.
      • Takahashi Y.
      • Iwami S.
      • Watashi K
      Different efficacies of neutralizing antibodies and antiviral drugs on SARS-CoV-2 Omicron subvariants, BA.1 and BA.2.
      ). However, the information reported here was largely based on full vaccination (typically two cycles) with the original index-SARS-CoV-2 virus-based vaccines. This was also collected during periods when SARS-COV-2 alpha and delta variants of concern were prevalent (
      • Looi M.K.
      Is covid-19 settling into a pattern?.
      ) and most people appeared to be natural-infection naïve (Table 3) and respond consistently over time and between vaccine cycles (
      • Tallantyre E.C.
      • Vickaryous N.
      • Anderson V.
      • Asardag A.N.
      • Baker D.
      • Bestwick J.
      • Bramhall K.
      • Chance R.
      • Evangelou N.
      • George K.
      • Giovannoni G.
      • Godkin A.
      • Grant L.
      • Harding K.E.
      • Hibbert A.
      • Ingram G.
      • Jones M.
      • Kang A.S.
      • Loveless S.
      • Moat S.J.
      • Robertson N.P.
      • Schmierer K.
      • Scurr M.J.
      • Shah S.N.
      • Simmons J.
      • Upcott M.
      • Willis M.
      • Jolles S.
      • Dobson R.
      COVID-19 vaccine response in people with multiple sclerosis.
      ;
      • Tallantyre E.C.
      • Scurr M.J.
      • Vickaryous N.
      • Richards A.
      • Anderson V.
      • Baker D.
      • Chance R.
      • Evangelou N.
      • George K.
      • Giovannoni G.
      • Harding K.E.
      • Hibbert A.
      • Ingram G.
      • Jolles S.
      • Jones M.
      • Kang A.S.
      • Loveless S.
      • Moat S.J.
      • Robertson N.P.
      • Rios F.
      • Schmierer K.
      • Willis M.
      • Godkin A.
      • Dobson R.
      Response to COVID-19 booster vaccinations in seronegative people with multiple sclerosis.
      ;
      • König M.
      • Torgauten H.M.
      • Tran T.T.
      • Holmøy T.
      • Vaage J.T.
      • Lund-Johansen F.
      • Nygaard G.O.
      Immunogenicity and Safety of a Third SARS-CoV-2 Vaccine Dose in Patients With Multiple Sclerosis and Weak Immune Response After COVID-19 Vaccination.
      ). Therefore, the circulating SARS-CoV-2 variant, may have had limited impact on the vaccine responses seen (Table 3).
      However, it is likely that the threshold of assay detection of SARS-CoV-2 antibodies is important in determining the level of seroconversion. Therefore, it is perhaps of interest that the high frequency of seroconversion seen notably in ozanimod-treated individuals was largely detected in studies using the SARS-CoV-2 receptor binding domain ECLIA Elecsys® assay (Table 3) (
      • Kantor D.
      SARS-CoV-2 vaccine response in RMS patients treated with ozanimod and other DMTs P13-4.008.
      ,(
      • Cree B.A.C.
      • Maddux R.
      • Bar-Or A.
      • Hartung H.P.
      • Kaur A.
      • Brown E.
      • Hu S.
      • Sheffield J.K.
      • Silva D.
      • Harris S.
      Serologic response and clinical outcomes of sars-cov-2 infection and vaccination in ozanimod-treated participants with relapsing multiple sclerosis.
      ). This seems to detect higher levels of seroconversion in fingolimod-treated, infection-naive (SARS-CoV-2 nucleocapsid antibody negative) individuals in comparison to the many different assays used (
      • Wu X.
      • Wang L.
      • Shen L.
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis.
      ;
      • Sormani M.P.
      • Inglese M.
      • Schiavetti I.
      • Carmisciano L.
      • Laroni A.
      • Lapucci C.
      • Da Rin G.
      • Serrati C.
      • Gandoglia I.
      • Tassinari T.
      • Perego G.
      • Brichetto G.
      • Gazzola P.
      • Mannironi A.
      • Stromillo M.L.
      • Cordioli C.
      • Landi D.
      • Clerico M.
      • Signoriello E.
      • Frau J.
      • Ferrò M.T.
      • Di Sapio A.
      • Pasquali L.
      • Ulivelli M.
      • Marinelli F.
      • Callari G.
      • Iodice R.
      • Liberatore G.
      • Caleri F.
      • Repice A.M.
      • Cordera S.
      • Battaglia M.A.
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      • Franciotta D.
      • Uccelli A.
      CovaXiMS study group on behalf of the Italian Covid-19 Alliance in MS. Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
      ;
      • Pitzalis M.
      • Idda M.L.
      • Lodde V.
      • Loizedda A.
      • Lobina M.
      • Zoledziewska M.
      • Virdis F.
      • Delogu G.
      • Pirinu F.
      • Marini M.G.
      • Mingoia M.
      • Frau J.
      • Lorefice L.
      • Fronza M.
      • Carmagnini D.
      • Carta E.
      • Orrù V.
      • Uzzau S.
      • Solla P.
      • Loi F.
      • Devoto M.
      • Steri M.
      • Fiorillo E.
      • Floris M.
      • Zarbo I.R.
      • Cocco E.
      • Cucca F.
      Effect of different disease-modifying therapies on humoral response to BNT162b2 vaccine in sardinian multiple sclerosis patients.
      ).These large studies may help skew the level of seroconversion observed, which can be quite heterogenous between fingolimod-related studies (
      • Wu X.
      • Wang L.
      • Shen L.
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis.
      ). As such a high level of seroconversion (n = 58/64. (90.6%)) was detected following tozinameran (BNT162b2) vaccination using the Elecsys® receptor binding domain antibody assay (
      • Sormani M.P.
      • Inglese M.
      • Schiavetti I.
      • Carmisciano L.
      • Laroni A.
      • Lapucci C.
      • Da Rin G.
      • Serrati C.
      • Gandoglia I.
      • Tassinari T.
      • Perego G.
      • Brichetto G.
      • Gazzola P.
      • Mannironi A.
      • Stromillo M.L.
      • Cordioli C.
      • Landi D.
      • Clerico M.
      • Signoriello E.
      • Frau J.
      • Ferrò M.T.
      • Di Sapio A.
      • Pasquali L.
      • Ulivelli M.
      • Marinelli F.
      • Callari G.
      • Iodice R.
      • Liberatore G.
      • Caleri F.
      • Repice A.M.
      • Cordera S.
      • Battaglia M.A.
      • Salvetti M.
      • Franciotta D.
      • Uccelli A.
      CovaXiMS study group on behalf of the Italian Covid-19 Alliance in MS. Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
      ). However, the median titre detected was only about 20 U/ml (
      • Sormani M.P.
      • Inglese M.
      • Schiavetti I.
      • Carmisciano L.
      • Laroni A.
      • Lapucci C.
      • Da Rin G.
      • Serrati C.
      • Gandoglia I.
      • Tassinari T.
      • Perego G.
      • Brichetto G.
      • Gazzola P.
      • Mannironi A.
      • Stromillo M.L.
      • Cordioli C.
      • Landi D.
      • Clerico M.
      • Signoriello E.
      • Frau J.
      • Ferrò M.T.
      • Di Sapio A.
      • Pasquali L.
      • Ulivelli M.
      • Marinelli F.
      • Callari G.
      • Iodice R.
      • Liberatore G.
      • Caleri F.
      • Repice A.M.
      • Cordera S.
      • Battaglia M.A.
      • Salvetti M.
      • Franciotta D.
      • Uccelli A.
      CovaXiMS study group on behalf of the Italian Covid-19 Alliance in MS. Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
      ). Likewise, in another similar fingolimod study, again a median antibody titre of only 26.7 U/ml (n = 71) was reported in infection-naïve, tozinameran-vaccinated individuals (
      • Pitzalis M.
      • Idda M.L.
      • Lodde V.
      • Loizedda A.
      • Lobina M.
      • Zoledziewska M.
      • Virdis F.
      • Delogu G.
      • Pirinu F.
      • Marini M.G.
      • Mingoia M.
      • Frau J.
      • Lorefice L.
      • Fronza M.
      • Carmagnini D.
      • Carta E.
      • Orrù V.
      • Uzzau S.
      • Solla P.
      • Loi F.
      • Devoto M.
      • Steri M.
      • Fiorillo E.
      • Floris M.
      • Zarbo I.R.
      • Cocco E.
      • Cucca F.
      Effect of different disease-modifying therapies on humoral response to BNT162b2 vaccine in sardinian multiple sclerosis patients.
      ). Importantly, it was reported that only 14/71 (19.1%) fingolimod-treated, infection-naïve individuals developed an index SARS-CoV-2 strain neutralizing titre of >133 U/ml occurred in fingolimod-treated individuals (
      • Pitzalis M.
      • Idda M.L.
      • Lodde V.
      • Loizedda A.
      • Lobina M.
      • Zoledziewska M.
      • Virdis F.
      • Delogu G.
      • Pirinu F.
      • Marini M.G.
      • Mingoia M.
      • Frau J.
      • Lorefice L.
      • Fronza M.
      • Carmagnini D.
      • Carta E.
      • Orrù V.
      • Uzzau S.
      • Solla P.
      • Loi F.
      • Devoto M.
      • Steri M.
      • Fiorillo E.
      • Floris M.
      • Zarbo I.R.
      • Cocco E.
      • Cucca F.
      Effect of different disease-modifying therapies on humoral response to BNT162b2 vaccine in sardinian multiple sclerosis patients.
      ). In contrast, the median SARS-CoV-2 receptor binding domain-specific antibody in ozanimod-treated, infection-naïve individuals was 138 U/ml (
      • Cree B.A.C.
      • Maddux R.
      • Bar-Or A.
      • Hartung H.P.
      • Kaur A.
      • Brown E.
      • Hu S.
      • Sheffield J.K.
      • Silva D.
      • Harris S.
      Serologic response and clinical outcomes of sars-cov-2 infection and vaccination in ozanimod-treated participants with relapsing multiple sclerosis.
      ). Although caution is needed in comparing different studies, this supports the view that at least ozanimod and perhaps other S1PR modulators, may allow a higher antibody titre to develop and thus create a potentially more effective vaccination response. Larger studies, meta-analysis of numerous smaller studies (
      • Wu X.
      • Wang L.
      • Shen L.
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis.
      ;
      • Gombolay G.Y.
      • Dutt M.
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ) or ideally clinical or experimental head to head studies will be required to determine whether there are indeed any real differences between the vaccine responses of the different S1PR modulators. However so far, this idea is suggested by some recent studies that contain responses to multiple different S1PR modulators (Table 3) (
      • Milo R.
      • Staun-Ram E.
      • Karussis D.
      • Karni A.
      • Hellmann M.A.
      • Bar-Haim E.
      • Miller A.
      Israeli Neuroimmunology study group on COVID-19 vaccination in multiple sclerosis
      Humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis: an Israeli multi-center experience following 3 vaccine doses.
      ;
      • Satyanarayan S.
      • Safi N.
      • Sorets T.
      • Filomena S.
      • Zhang Y.
      • Klineova S.
      • Fabian M.
      • Horng S.
      • Tankou S.
      • Miller A.
      • Krieger S.
      • Lublin F.
      • Sumowski J.
      • Katz Sand I.
      ;
      • Akgün K.
      • Dunsche M.
      • Katoul Al Rahbani G.
      • Woopen C.
      • Ziemssen T
      Different type and timing of S1P receptor modulator therapy impacts T and B cell response after SARS-CoV2 vaccination P316.
      ).
      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 X.
      • Wang L.
      • Shen L.
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis.
      ;
      • Gombolay G.Y.
      • Dutt M.
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ;
      • Tallantyre E.C.
      • Vickaryous N.
      • Anderson V.
      • Asardag A.N.
      • Baker D.
      • Bestwick J.
      • Bramhall K.
      • Chance R.
      • Evangelou N.
      • George K.
      • Giovannoni G.
      • Godkin A.
      • Grant L.
      • Harding K.E.
      • Hibbert A.
      • Ingram G.
      • Jones M.
      • Kang A.S.
      • Loveless S.
      • Moat S.J.
      • Robertson N.P.
      • Schmierer K.
      • Scurr M.J.
      • Shah S.N.
      • Simmons J.
      • Upcott M.
      • Willis M.
      • Jolles S.
      • Dobson R.
      COVID-19 vaccine response in people with multiple sclerosis.
      ;
      • Meyer-Arndt L.
      • Braun J.
      • Fauchere F.
      • Vanshylla K.
      • Loyal L.
      • Henze L.
      • Kruse B.
      • Dingeldey M.
      • Jürchott K.
      • Mangold M.
      • Maraj A.
      • Braginets A.
      • Böttcher C.
      • Nitsche A.
      • de la Rosa K.
      • Ratswohl C.
      • Sawitzki B.
      • Holenya P.
      • Reimer U.
      • Sander L.E.
      • Klein F.
      • Paul F.
      • Bellmann-Strobl J.
      • Thiel A.
      • Giesecke-Thiel C.
      SARS-CoV-2 mRNA vaccinations fail to elicit humoral and cellular immune responses in patients with multiple sclerosis receiving fingolimod.
      ;
      • Wolf A.S.
      • Ravussin A.
      • König M.
      • Øverås M.H.
      • Solum S.
      • Fadum Kjønstad I.
      • Chopra A.
      • Holmøy T.
      • Harbo H.F.
      • Watterdal S.S.
      • Kaasen Jørgensenn K.
      • August Høgestøl F.
      • Torgils Vaage J.
      • Celius E.G.
      • Lund-Johansen F.
      • Munthe L.A.
      • Owren Nygaard G.
      • Mjaaland S
      T cell responses to SARS-CoV-2 vaccination in people with multiple sclerosis differ between disease-modifying therapies.
      ). The peripheral blood T cell responses in people treated with the more recent S1PR modulators have been inconsistent and further study is required (
      • Ziemssen T.
      • Groth M.
      • Rauser B.
      • Bopp T.
      Assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod-treated patients: a nonrandomized controlled clinical trial (AMA-VACC).
      ;
      • Kantor D.
      SARS-CoV-2 vaccine response in RMS patients treated with ozanimod and other DMTs P13-4.008.
      ;