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

  • Author Footnotes
    # Equal contribution.
    David Baker
    Correspondence
    Correspondence: Professor David Baker. BartsMS, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London. 4 Newark Street, London E1 2AT, United Kingdom.
    Footnotes
    # 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
    # Equal contribution.
    Eugenia Forte
    Footnotes
    # 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
    # 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)

      1. Multiple sclerosis and disease modifying treatments

      Multiple sclerosis (MS) is an immune-mediated, demyelinating and neurodegenerative disease of the central nervous system (CNS) that is the major cause of non-traumatic disability in young adults (
      • Dobson R
      • Giovannoni G.
      Multiple sclerosis - a review.
      ). Relapsing disease is associated with mononuclear cell inflammation that enters and becomes sequestered in the CNS and supports the generation of innate immune/glial-cell based inflammation, which promotes the development of accumulating neurodegeneration and disability (
      • Dobson R
      • Giovannoni G.
      Multiple sclerosis - a review.
      ). Active inflammation, seen by new lesion activity on imaging and/or clinical relapse, can be targeted by a large number of disease modifying treatments (
      • Dobson R
      • Giovannoni G.
      Multiple sclerosis - a review.
      ,
      • Lublin FD
      • Reingold SC
      • Cohen JA
      • Cutter GR
      • Sørensen PS
      • Thompson AJ
      • Wolinsky JS
      • Balcer LJ
      • Banwell B
      • Barkhof F
      • Bebo Jr, B
      • Calabresi PA
      • Clanet M
      • Comi G
      • Fox RJ
      • Freedman MS
      • Goodman AD
      • Inglese M
      • Kappos L
      • Kieseier BC
      • Lincoln JA
      • Lubetzki C
      • Miller AE
      • Montalban X
      • O'Connor PW
      • Petkau J
      • Pozzilli C
      • Rudick RA
      • Sormani MP
      • Stüve O
      • Waubant E
      • Polman CH
      Defining the clinical course of multiple sclerosis: the 2013 revisions.
      ). Whilst MS is thought to be driven by pathogenic T cells, it is evident that all effective immunotherapies limit the capacity of B cell subsets to enter the CNS (
      • Dobson R
      • Giovannoni G.
      Multiple sclerosis - a review.
      ,
      • Baker D
      • Marta M
      • Pryce G
      • Giovannoni G
      • Schmierer K
      Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis.
      ). These therapeutic monoclonal antibodies and small molecules target the adaptive immune response to act largely via inhibition of immune-activation, peripheral lymphocyte depletion or lymphocyte migration-inhibition (
      • Dobson R
      • Giovannoni G.
      Multiple sclerosis - a review.
      ).
      Current migration inhibitors affect both T and B cells, which are central, interacting parts of the immune system that deals with infection and vaccination (
      • Mehling M
      • Brinkmann V
      • Antel J
      • Bar-Or A
      • Goebels N
      • Vedrine C
      • Kristofic C
      • Kuhle J
      • Lindberg RL
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ,
      • Gergely P
      • Nuesslein-Hildesheim B
      • Guerini D
      • Brinkmann V
      • Traebert M
      • Bruns C
      • Pan S
      • Gray NS
      • Hinterding K
      • Cooke NG
      • Groenewegen A
      • Vitaliti A
      • Sing T
      • Luttringer O
      • Yang J
      • Gardin A
      • Wang N
      • Crumb Jr, WJ
      • 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.
      ,
      • Jurcevic S
      • Juif PE
      • 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.
      ,
      • Petersone L
      • Edner NM
      • Ovcinnikovs V
      • Heuts F
      • Ross EM
      • Ntavli E
      • Wang CJ
      • Walker LSK.
      ,
      • Harris S
      • Tran JQ
      • Southworth H
      • Spencer CM
      • Cree BAC
      • Zamvil SS.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ). Therefore, there was major concern at the beginning of the coronavirus 2019 (COVID-19) pandemic, caused by severe acute respiratory corona virus two (SAR-CoV-2) infection, about the risks posed to people taking immunosuppressive treatments, particularly as severe disease was associated with lymphopenia (
      • Wang D
      • Hu B
      • Hu C
      • Zhu F
      • Liu X
      • Zhang J
      • Wang B
      • Xiang H
      • Cheng Z
      • Xiong Y
      • Zhao Y
      • Li Y
      • Wang X
      • Peng Z.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      ,
      • Baker D
      • Amor S
      • Kang AS
      • Schmierer K
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ). This led to treatment delays, cessation and switching of agents to avoid lymphopenia and to allow more rapid drug wash-outs in case of infection (
      • Baker D
      • Amor S
      • Kang AS
      • Schmierer K
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ). With time, SARS-CoV-2 vaccines and anti-viral agents have been developed to fight the disease that has killed millions of people and created economic havoc (
      • Khoury DS
      • Cromer D
      • Reynaldi A
      • Schlub TE
      • Wheatley AK
      • Juno JA
      • Subbarao K
      • Kent SJ
      • Triccas JA
      • Davenport MP.
      Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.
      ,
      • 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 GY
      • Dutt M
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ,
      • Sendi P
      • Razonable RR
      • Nelson SB
      • Soriano A
      • Gandhi RT.
      First-generation oral antivirals against SARS-CoV-2.
      ,
      • Richards F
      • Kodjamanova P
      • Chen X
      • Li N
      • Atanasov P
      • Bennetts L
      • Patterson BJ
      • Yektashenas B
      • Mesa-Frias M
      • Tronczynski K
      • Buyukkaramikli N
      • El Khoury AC.
      Economic Burden of COVID-19: A Systematic Review.
      ). However, this has created further challenges for use in immunosuppressed people (
      • Baker D
      • Amor S
      • Kang AS
      • Schmierer K
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ), especially as this is occurring within a landscape of global viral evolution and the generation of circulating SARS-CoV-2 variants that have different morbidities, contagion and immune-escape (
      • Chen Z
      • Zhang Y
      • Wang M
      • Islam MS
      • Liao P
      • Hu Y
      • Chen X.
      Humoral and cellular immune responses of COVID-19 vaccines against SARS-CoV-2 omicron variant: a systemic review.
      ,
      • Shrestha LB
      • Foster C
      • Rawlinson W
      • Tedla N
      • Bull RA.
      Evolution of the SARS-CoV-2 omicron variants BA.1 to BA.5: Implications for immune escape and transmission.
      ). However, as immune-escape is in part attributable to viral evolution in immunosuppressed individuals (
      • Weigang S
      • Fuchs J
      • Zimmer G
      • Schnepf D
      • Kern L
      • Beer J
      • Luxenburger H
      • Ankerhold J
      • Falcone V
      • Kemming J
      • Hofmann M
      • Thimme R
      • Neumann-Haefelin C
      • Ulferts S
      • Grosse R
      • Hornuss D
      • Tanriver Y
      • Rieg S
      • Wagner D
      • Huzly D
      • Schwemmle M
      • Panning M
      • Kochs G.
      Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants.
      ,
      • Scherer EM
      • Babiker A
      • Adelman MW
      • Allman B
      • Key A
      • Kleinhenz JM
      • Langsjoen RM
      • Nguyen PV
      • Onyechi I
      • Sherman JD
      • Simon TW
      • Soloff H
      • Tarabay J
      • Varkey J
      • Webster AS
      • Weiskopf D
      • Weissman DB
      • Xu Y
      • Waggoner JJ
      • Koelle K
      • Rouphael N
      • Pouch SM
      • Piantadosi A.
      SARS-CoV-2 evolution and immune escape in immunocompromised patients.
      ), it is important to optimise anti-viral therapy within the need to effectively control immune-mediated diseases.

      2. Coronavirus-19 disease and issues with SARS-CoV-2 vaccination

      As data emerged about COVID-19 pathogenesis it became evident that lymphopenia was largely a consequence of severe COVID-19 and that coagulation issues were central to pathology and morbidity (
      • Baker D
      • Roberts CAK
      • Pryce G
      • Kang AS
      • Marta M
      • Reyes S
      • Schmierer K
      • Giovannoni G
      • Amor S
      COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.
      ). The biology of the disease modifying MS treatments indicates that they have limited to no impact on coagulation and microthrombi formation and vice versa (
      • Farrokhi M
      • Beni AA
      • Etemadifar M
      • Rezaei A
      • Rivard L
      • Zadeh AR
      • Sedaghat N
      • Ghadimi M.
      Effect of fingolimod on platelet count among multiple sclerosis patients.
      ). Furthermore, all MS treatments are largely targeted to the adaptive immune arm and seem to have limited activity on the innate system, which appears to be important in anti-viral immunity and some elements of pathology. This suggested that treatment of MS was less of a risk factor than initially feared (
      • Baker D
      • Amor S
      • Kang AS
      • Schmierer K
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ,
      • Baker D
      • Roberts CAK
      • Pryce G
      • Kang AS
      • Marta M
      • Reyes S
      • Schmierer K
      • Giovannoni G
      • Amor S
      COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.
      ). Indeed, it was found that susceptibility of people with MS to the SARS-CoV-2 virus was related largely to the risk factors seen within the general population, such as age and co-morbidities, with the addition of disability due to MS (
      • Sormani MP
      • 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 MA
      • 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 JA
      • 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 AB
      • Braune S
      • Stahmann A
      • Middleton R
      • Salter A
      • Fox RJ
      • van der Walt A
      • Butzkueven H
      • Alroughani R
      • Ozakbas S
      • Rojas JI
      • van der Mei I
      • Nag N
      • Ivanov R
      • Sciascia do Olival G
      • Dias AE
      • Magyari M
      • Brum D
      • Mendes MF
      • Alonso RN
      • Nicholas RS
      • Bauer J
      • Chertcoff AS
      • Zabalza A
      • Arrambide G
      • Fidao A
      • Comi G
      • Peeters L.
      Associations of disease-modifying therapies with COVID-19 severity in multiple sclerosis.
      ). Importantly, most disease modifying treatments were not associated with a worse prognosis following infection (
      • Sormani MP
      • 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 MA
      • 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 JA
      • 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 AB
      • Braune S
      • Stahmann A
      • Middleton R
      • Salter A
      • Fox RJ
      • van der Walt A
      • Butzkueven H
      • Alroughani R
      • Ozakbas S
      • Rojas JI
      • van der Mei I
      • Nag N
      • Ivanov R
      • Sciascia do Olival G
      • Dias AE
      • Magyari M
      • Brum D
      • Mendes MF
      • Alonso RN
      • Nicholas RS
      • Bauer J
      • Chertcoff AS
      • 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 JA
      • Moreau Y
      • Edan G
      • Sharmin S
      • Spelman T
      • McBurney R
      • Schmidt H
      • Bergmann AB
      • Braune S
      • Stahmann A
      • Middleton RM
      • Salter A
      • Bebo B
      • Van der Walt A
      • Butzkueven H
      • Ozakbas S
      • Boz C
      • Karabudak R
      • Alroughani R
      • Rojas JI
      • van der Mei IA
      • Sciascia do Olival G
      • Magyari M
      • Alonso RN
      • Nicholas RS
      • Chertcoff AS
      • de Torres AZ
      • Arrambide G
      • Nag N
      • Descamps A
      • Costers L
      • Dobson R
      • Miller A
      • Rodrigues P
      • Prčkovska V
      • Comi G
      • Peeters LM
      Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity.
      ). However, a modestly worse course of infection seemed to occur in some individuals who were continuously B cell depleted with either ocrelizumab or rituximab, CD20-depleting agents (
      • Sormani MP
      • 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 MA
      • 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 JA
      • 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 AB
      • Braune S
      • Stahmann A
      • Middleton R
      • Salter A
      • Fox RJ
      • van der Walt A
      • Butzkueven H
      • Alroughani R
      • Ozakbas S
      • Rojas JI
      • van der Mei I
      • Nag N
      • Ivanov R
      • Sciascia do Olival G
      • Dias AE
      • Magyari M
      • Brum D
      • Mendes MF
      • Alonso RN
      • Nicholas RS
      • Bauer J
      • Chertcoff AS
      • 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 JA
      • Moreau Y
      • Edan G
      • Sharmin S
      • Spelman T
      • McBurney R
      • Schmidt H
      • Bergmann AB
      • Braune S
      • Stahmann A
      • Middleton RM
      • Salter A
      • Bebo B
      • Van der Walt A
      • Butzkueven H
      • Ozakbas S
      • Boz C
      • Karabudak R
      • Alroughani R
      • Rojas JI
      • van der Mei IA
      • Sciascia do Olival G
      • Magyari M
      • Alonso RN
      • Nicholas RS
      • Chertcoff AS
      • de Torres AZ
      • Arrambide G
      • Nag N
      • Descamps A
      • Costers L
      • Dobson R
      • Miller A
      • Rodrigues P
      • Prčkovska V
      • Comi G
      • Peeters LM
      Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity.
      ,
      • Reder AT
      • Centonze D
      • Naylor ML
      • Nagpal A
      • Rajbhandari R
      • Altincatal A
      • Kim M
      • Berdofe A
      • Radhakrishnan M
      • Jung E
      • Sandrock AW
      • Smirnakis K
      • Popescu C
      • de Moor C
      COVID-19 in patients with multiple sclerosis: ssociations with disease-modifying therapies.
      ). Furthermore, CD20-depletion was predicted to (
      • Baker D
      • Roberts CAK
      • Pryce G
      • Kang AS
      • Marta M
      • Reyes S
      • Schmierer K
      • Giovannoni G
      • Amor S
      COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.
      ) and subsequently shown to limit seroconversion to infection and SARS-CoV-2 vaccines, without major impact on T cell responses, until therapeutic-antibody disappears and B cell repopulation is allowed to occur (
      • 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 GY
      • Dutt M
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ,
      • Madelon N
      • Lauper K
      • Breville G
      • Sabater Royo I
      • Goldstein R
      • DO Andrey
      • Grifoni A
      • Sette A
      • Kaiser L
      • Siegrist CA
      • Finckh A
      • Lalive PH
      • Didierlaurent AM
      • Eberhardt CS.
      Robust T cell responses in anti-CD20 treated patients following COVID-19 vaccination: a prospective cohort study.
      ,
      • Baker D
      • MacDougall A
      • Kang AS
      • Schmierer K
      • Giovannoni G
      • Dobson R.
      Seroconversion following COVID-19 vaccination: Can we optimize protective response in CD20-treated individuals?.
      ,
      • Sormani MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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.
      ,
      • Pitzalis M
      • Idda ML
      • Lodde V
      • Loizedda A
      • Lobina M
      • Zoledziewska M
      • Virdis F
      • Delogu G
      • Pirinu F
      • Marini MG
      • 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 IR
      • Cocco E
      • Cucca F.
      Effect of different disease-modifying therapies on humoral response to BNT162b2 vaccine in sardinian multiple sclerosis patients.
      ,
      • Tallantyre EC
      • Vickaryous N
      • Anderson V
      • Asardag AN
      • Baker D
      • Bestwick J
      • Bramhall K
      • Chance R
      • Evangelou N
      • George K
      • Giovannoni G
      • Godkin A
      • Grant L
      • Harding KE
      • Hibbert A
      • Ingram G
      • Jones M
      • Kang AS
      • Loveless S
      • Moat SJ
      • Robertson NP
      • Schmierer K
      • Scurr MJ
      • Shah SN
      • Simmons J
      • Upcott M
      • Willis M
      • Jolles S
      • Dobson R.
      COVID-19 Vaccine Response in People with Multiple Sclerosis.
      ,
      • Tallantyre EC
      • Scurr MJ
      • Vickaryous N
      • Richards A
      • Anderson V
      • Baker D
      • Chance R
      • Evangelou N
      • George K
      • Giovannoni G
      • Harding KE
      • Hibbert A
      • Ingram G
      • Jolles S
      • Jones M
      • Kang AS
      • Loveless S
      • Moat SJ
      • Robertson NP
      • Rios F
      • Schmierer K
      • Willis M
      • Godkin A
      • Dobson R.
      Response to COVID-19 booster vaccinations in seronegative people with multiple sclerosis.
      ). CD20-depletion prevents the generation of immature/naïve B cells capable of producing novel antibody-responses that may have included the inability to form protective, cross-reactive antibodies following natural infection with other (corona)viruses, which could prevent/protect against subsequent SARS-COV-2 infection (
      • Baker D
      • Roberts CAK
      • Pryce G
      • Kang AS
      • Marta M
      • Reyes S
      • Schmierer K
      • Giovannoni G
      • Amor S
      COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.
      ,
      • Fraley E
      • LeMaster C
      • Banerjee D
      • Khanal S
      • Selvarangan R
      • Bradley T.
      Cross-reactive antibody immunity against SARS-CoV-2 in children and adults.
      ,
      • Klompus S
      • Leviatan S
      • Vogl T
      • Mazor RD
      • Kalka IN
      • Stoler-Barak L
      • Nathan N
      • Peres A
      • Moss L
      • Godneva A
      • Kagan Ben Tikva S
      • Shinar E
      • Dvashi HC
      • Gabizon R
      • London N
      • Diskin R
      • Yaari G
      • Weinberger A
      • Shulman Z
      • Segal E
      Cross-reactive antibodies against human coronaviruses and the animal coronavirome suggest diagnostics for future zoonotic spillovers.
      ).
      In contrast fingolimod (Figure 1), which is a lymphocyte migration inhibitor, was not associated with a worse outcome following natural SARS-CoV-2 infection (
      • Sormani MP
      • 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 MA
      • 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 JA
      • 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 AB
      • Braune S
      • Stahmann A
      • Middleton R
      • Salter A
      • Fox RJ
      • van der Walt A
      • Butzkueven H
      • Alroughani R
      • Ozakbas S
      • Rojas JI
      • van der Mei I
      • Nag N
      • Ivanov R
      • Sciascia do Olival G
      • Dias AE
      • Magyari M
      • Brum D
      • Mendes MF
      • Alonso RN
      • Nicholas RS
      • Bauer J
      • Chertcoff AS
      • 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 JA
      • Moreau Y
      • Edan G
      • Sharmin S
      • Spelman T
      • McBurney R
      • Schmidt H
      • Bergmann AB
      • Braune S
      • Stahmann A
      • Middleton RM
      • Salter A
      • Bebo B
      • Van der Walt A
      • Butzkueven H
      • Ozakbas S
      • Boz C
      • Karabudak R
      • Alroughani R
      • Rojas JI
      • van der Mei IA
      • Sciascia do Olival G
      • Magyari M
      • Alonso RN
      • Nicholas RS
      • Chertcoff AS
      • de Torres AZ
      • Arrambide G
      • Nag N
      • Descamps A
      • Costers L
      • Dobson R
      • Miller A
      • Rodrigues P
      • Prčkovska V
      • Comi G
      • Peeters LM
      Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity.
      ,
      • Reder AT
      • Centonze D
      • Naylor ML
      • Nagpal A
      • Rajbhandari R
      • Altincatal A
      • Kim M
      • Berdofe A
      • Radhakrishnan M
      • Jung E
      • Sandrock AW
      • Smirnakis K
      • Popescu C
      • de Moor C
      COVID-19 in patients with multiple sclerosis: ssociations with disease-modifying therapies.
      ,
      • Sullivan R
      • Kilaru A
      • Hemmer B
      • Campbell Cree BA
      • Greenberg BM
      • Kundu U
      • Hach T
      • DeLasHeras V
      • Ward BJ
      • Berger J.
      COVID-19 infection in fingolimod- or siponimod-treated patients: case series.
      ). Perhaps consistent with this, the majority of people on fingolimod appeared to seroconvert, albeit sometimes with lower antibody titres following a natural SARS-CoV-2 infection (
      • Bigaut K
      • Kremer L
      • Fabacher T
      • Lanotte L
      • Fleury MC
      • Collongues N
      • de Seze J.
      Impact of Disease-Modifying Treatments of Multiple Sclerosis on Anti-SARS-CoV-2 Antibodies: An Observational Study.
      ,
      • Bsteh G
      • Dürauer S
      • Assar H
      • Hegen H
      • Heschl B
      • Leutmezer F
      • Pauli FD
      • Gradl C
      • Traxler G
      • Zulehner G
      • Rommer P
      • Wipfler P
      • Guger M
      • Höftberger R
      • Enzinger C
      • Berger T.
      Humoral immune response after COVID-19 in multiple sclerosis: A nation-wide Austrian study.
      ,
      • van Kempen ZLE
      • Strijbis EMM
      • Al MMCT
      • Steenhuis M
      • Uitdehaag BMJ
      • Rispens T
      • Killestein J
      SARS-CoV-2 Antibodies in Adult Patients With Multiple Sclerosis in the Amsterdam MS Cohort.
      ,
      • Zabalza A
      • Cárdenas-Robledo S
      • Tagliani P
      • Arrambide G
      • Otero-Romero S
      • Carbonell-Mirabent P
      • Rodriguez-Barranco M
      • Rodríguez-Acevedo B
      • JL Restrepo Vera
      • Resina-Salles M
      • Midaglia L
      • Vidal-Jordana A
      • Río J
      • Galan I
      • Castillo J
      • Á Cobo-Calvo
      • Comabella M
      • Nos C
      • Sastre-Garriga J
      • Tintore M
      • Montalban X
      COVID-19 in multiple sclerosis patients: susceptibility, severity risk factors and serological response.
      ,
      • Louapre C
      • Ibrahim M
      • Maillart E
      • Abdi B
      • Papeix C
      • Stankoff B
      • Dubessy AL
      • Bensa-Koscher C
      • Créange A
      • Chamekh Z
      • Lubetzki C
      • Marcelin AG
      • Corvol JC
      • Pourcher V
      COVISEP and Bio-coco-neuroscience study group
      Anti-CD20 therapies decrease humoral immune response to SARS-CoV-2 in patients with multiple sclerosis or neuromyelitis optica spectrum disorders.
      ,
      • Sormani MP
      • Schiavetti I
      • Landi D
      • Carmisciano L
      • De Rossi N
      • Cordioli C
      • Moiola L
      • Radaelli M
      • Immovilli P
      • Capobianco M
      • V Brescia Morra
      • Trojano M
      • Tedeschi G
      • Comi G
      • Battaglia MA
      • Patti F
      • Fragoso YD
      • Sen S
      • Siva A
      • Furlan R
      • Salvetti M
      MuSC-19 Study Group
      SARS-CoV-2 serology after COVID-19 in multiple sclerosis: An international cohort study.
      ). Similarly, modest reductions in antibody titres notably with other vaccines, have been seen in fingolimod-treated individuals (
      • Boulton C
      • Meiser K
      • David OJ
      • Schmouder R.
      Pharmacodynamic effects of steady-state fingolimod on antibody response in healthy volunteers: a 4-week, randomized, placebo-controlled, parallel-group, multiple-dose study.
      ,
      • Kappos L
      • Mehling M
      • Arroyo R
      • Izquierdo G
      • Selmaj K
      • Curovic-Perisic V
      • Keil A
      • Bijarnia M
      • Singh A
      • von Rosenstiel P
      Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis.
      ,
      • Zoehner G
      • Miclea A
      • Salmen A
      • Kamber N
      • Diem L
      • Friedli C
      • Bagnoud M
      • Ahmadi F
      • Briner M
      • Sédille-Mostafaie N
      • Kilidireas C
      • Stefanis L
      • Chan A
      • Hoepner R
      • Evangelopoulos ME.
      Reduced serum immunoglobulin G concentrations in multiple sclerosis: prevalence and association with disease-modifying therapy and disease course.
      ). 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 X
      • Wang L
      • Shen L
      • Tang K.
      Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: A meta-analysis.
      ,
      • Gombolay GY
      • Dutt M
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ,
      • Tallantyre EC
      • Vickaryous N
      • Anderson V
      • Asardag AN
      • Baker D
      • Bestwick J
      • Bramhall K
      • Chance R
      • Evangelou N
      • George K
      • Giovannoni G
      • Godkin A
      • Grant L
      • Harding KE
      • Hibbert A
      • Ingram G
      • Jones M
      • Kang AS
      • Loveless S
      • Moat SJ
      • Robertson NP
      • Schmierer K
      • Scurr MJ
      • Shah SN
      • Simmons J
      • Upcott M
      • Willis M
      • Jolles S
      • Dobson R.
      COVID-19 Vaccine Response in People with Multiple Sclerosis.
      ,
      • Tallantyre EC
      • Scurr MJ
      • Vickaryous N
      • Richards A
      • Anderson V
      • Baker D
      • Chance R
      • Evangelou N
      • George K
      • Giovannoni G
      • Harding KE
      • Hibbert A
      • Ingram G
      • Jolles S
      • Jones M
      • Kang AS
      • Loveless S
      • Moat SJ
      • Robertson NP
      • Rios F
      • Schmierer K
      • Willis M
      • Godkin A
      • Dobson R.
      Response to COVID-19 booster vaccinations in seronegative people with multiple sclerosis.
      ,
      • Achiron A
      • Mandel M
      • Dreyer-Alster S
      • Harari G
      • Magalashvili D
      • Sonis P
      • Dolev M
      • Menascu S
      • Flechter S
      • Falb R
      • Gurevich M.
      Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.
      ,
      • 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 LE
      • 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.
      ). 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 I
      • Cordioli C
      • Stromillo ML
      • Teresa Ferrò M
      • Laroni A
      • Cocco E
      • Cola G
      • Pasquali L
      • Rilla MT
      • Signoriello E
      • Iodice R
      • Di Sapio A
      • Lanzillo R
      • Caleri F
      • Annovazzi P
      • Conte A
      • Liberatore G
      • Ruscica F
      • Docimo R
      • Bonavita S
      • Ulivelli M
      • Cavalla P
      • Patti F
      • Ferraro D
      • Clerico M
      • Immovilli P
      • Di Filippo M
      • Salvetti M
      • Sormani MP
      Breakthrough SARS-CoV-2 infections in MS patients on disease-modifying therapies.
      ,
      • Garjani A
      • Patel S
      • Bharkhada D
      • Rashid W
      • Coles A
      • Law GR
      • Evangelou N.
      Impact of mass vaccination on SARS-CoV-2 infections among multiple sclerosis patients taking immunomodulatory disease-modifying therapies in England.
      ,
      • Bsteh G
      • Gradl C
      • Heschl B
      • Hegen H
      • F Di Pauli
      • Assar H
      • Leutmezer F
      • Traxler G
      • Krajnc N
      • Zulehner G
      • Hiller MS
      • Rommer P
      • Wipfler P
      • Guger M
      • Enzinger C
      • Berger T
      • investigators AUT-MuSC
      Impact of vaccination on COVID-19 outcome in multiple sclerosis.
      ,
      • Sormani MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Cocco E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Pizzorno M
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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.
      ). Importantly, this was seen even before the time when circulating SARS-CoV-2 variants of concern, notably omicron variants, required high vaccine-induced antibody titres to protect from infection compared to the initial SARS-CoV-2 variants (
      • Chen Z
      • Zhang Y
      • Wang M
      • Islam MS
      • Liao P
      • Hu Y
      • Chen X.
      Humoral and cellular immune responses of COVID-19 vaccines against SARS-CoV-2 omicron variant: a systemic review.
      ,
      • Sormani MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Cocco E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Pizzorno M
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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.
      ,
      • Cheng SMS
      • Mok CKP
      • Leung YWY
      • Ng SS
      • Chan KCK
      • Ko FW
      • Chen C
      • Yiu K
      • Lam BHS
      • Lau EHY
      • Chan KKP
      • Luk LLH
      • Li JKC
      • Tsang LCH
      • Poon LLM
      • Hui DSC
      • Peiris M.
      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 HM
      • Selvaraj M
      • Liu C
      • Mentzer AJ
      • Supasa P
      • Duyvesteyn HME
      • Das R
      • Skelly D
      • Ritter TG
      • Amini A
      • Bibi S
      • Adele S
      • Johnson SA
      • Constantinides B
      • Webster H
      • Temperton N
      • Klenerman P
      • Barnes E
      • Dunachie SJ
      • Crook D
      • Pollard AJ
      • Lambe T
      • Goulder P
      • Paterson NG
      • Williams MA
      • Hall DR
      • Fry EE
      • Huo J
      • Mongkolsapaya J
      • Ren J
      • Stuart DI
      • Screaton GR
      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 AS
      • Schmierer K
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ,
      • Sormani MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Cocco E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Pizzorno M
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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 (Figure 1) (
      • Al-Salama ZT.
      • Siponimod
      ,
      • Lamb YN.
      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.
      Figure 1
      Figure 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 CC
      • Eveslage M
      • Meuth SG
      • 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 (Figure 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 LJ.
      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 JG
      • Schwab SR.
      Sphingosine-1-Phosphate and Lymphocyte Egress from Lymphoid Organs.
      ). The current S1PR modulators have distinct S1PR binding affinities, pharmacokinetics and different use-indications (Figure 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 ZT.
      • Siponimod
      ,
      • Lamb YN.
      Ozanimod: First Approval.
      ,
      • Markham A.
      Ponesimod: First Approval.
      ,
      • Scott LJ.
      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 FD
      • Reingold SC
      • Cohen JA
      • Cutter GR
      • Sørensen PS
      • Thompson AJ
      • Wolinsky JS
      • Balcer LJ
      • Banwell B
      • Barkhof F
      • Bebo Jr, B
      • Calabresi PA
      • Clanet M
      • Comi G
      • Fox RJ
      • Freedman MS
      • Goodman AD
      • Inglese M
      • Kappos L
      • Kieseier BC
      • Lincoln JA
      • Lubetzki C
      • Miller AE
      • Montalban X
      • O'Connor PW
      • Petkau J
      • Pozzilli C
      • Rudick RA
      • Sormani MP
      • Stüve O
      • Waubant E
      • Polman CH
      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 ZT.
      • Siponimod
      ,
      • Lamb YN.
      Ozanimod: First Approval.
      ,
      • Markham A.
      Ponesimod: First Approval.
      ,
      • Scott LJ.
      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 AA
      • 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 AS
      • 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 hours1 week
      Siponimod1,54h30 hours10 days
      Ozanimod1,56-8h21h/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 JV
      • Yan YG
      • Zhang P
      • Hargreaves R
      • Kumar G
      • Palmisano M
      • Tran JQ.
      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 ZT.
      • Siponimod
      ,
      • 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 YN.
      Ozanimod: First Approval.
      ,
      • Surapaneni S
      • Yerramilli U
      • Bai A
      • Dalvie D
      • Brooks J
      • Wang X
      • Selkirk JV
      • Yan YG
      • Zhang P
      • Hargreaves R
      • Kumar G
      • Palmisano M
      • Tran JQ.
      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 JJ
      • 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 TC
      • Legangneux E
      Impact of siponimod on vaccination response in a randomized, placebo-controlled study.
      ,
      • Rauser B
      • Ziemssen T
      • Groth M
      • Bopp T
      AMA-VACC: Clinical trial assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod treated patients with secondary progressive multiple sclerosis (P1-1.virtual).
      *), (
      • 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
      S1P

      Fingolimod

      Fingolimod-P
      0.47nM
      competitive radio-ligand binding


      300nM
      competitive radio-ligand binding


      0.21nM
      competitive radio-ligand binding
      0.31nM
      competitive radio-ligand binding


      >10,000nM
      competitive radio-ligand binding


      >10,000nM
      competitive radio-ligand binding
      0.17nM
      competitive radio-ligand binding


      >10,000nM
      competitive radio-ligand binding


      5.0nM
      competitive radio-ligand binding
      95 nM
      competitive radio-ligand binding


      >5,000nM
      competitive radio-ligand binding


      5.9 nM
      competitive radio-ligand binding
      0.61nM
      competitive radio-ligand binding


      2623nM
      competitive radio-ligand binding


      0.59nM
      competitive radio-ligand binding
      83
      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
      69
      Siponimod0.39nM
      gamma GTPS or
      >10,000nM
      gamma GTPS or
      > 1,000nM
      gamma GTPS or
      750nM
      gamma GTPS or
      0.98nM
      gamma GTPS or
      5
      OzanimodFingolimod-P

      Siponimod
      0.41nM
      gamma GTPS or


      0.27nM
      gamma GTPS or


      0.39nM
      gamma GTPS or
      >10,000nM
      gamma GTPS or


      >10,000nM
      gamma GTPS or


      >10,000nM
      gamma GTPS or
      >10,000nM
      gamma GTPS or


      0.90nM
      gamma GTPS or


      >10,000nM
      gamma GTPS or
      >7,865nM
      beta-arrestin binding assays.


      345nM
      beta-arrestin binding assays.


      920nM
      beta-arrestin binding assays.
      11nM
      gamma GTPS or


      0.5nM
      gamma GTPS or


      0.38nM
      gamma GTPS or
      72
      Ponesimod

      S1P
      5.7nM
      gamma GTPS or


      25.3nM
      gamma GTPS or
      >10,000nM
      gamma GTPS or


      43.9M
      gamma GTPS or
      105nMa
      gamma GTPS or


      0.7nM
      gamma GTPS or
      1,108nM
      gamma GTPS or
      ,
      Maximal effect at 10,000nM 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: 0.5mg fingolimod, 1mg siponimod, 0.92mg ozanimod or 20mg ponesimod.
      164nM
      gamma GTPS or
      59.1nM
      gamma GTPS or
      ,
      Maximal effect at 10,000nM 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: 0.5mg fingolimod, 1mg siponimod, 0.92mg ozanimod or 20mg ponesimod.


      1.1nM
      gamma GTPS or
      71
      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 10,000nM 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: 0.5mg fingolimod, 1mg siponimod, 0.92mg ozanimod or 20mg ponesimod.
      Fingolimod binds to S1PR1, S1PR3, S1PR4, and S1PR5, which have distinct tissue distributions that will impact on its function (Figure 1; Table 2) (
      • Brinkmann V
      • Davis MD
      • Heise CE
      • Albert R
      • Cottens S
      • Hof R
      • Bruns C
      • Prieschl E
      • Baumruker T
      • Hiestand P
      • Foster CA
      • Zollinger M
      • Lynch KR.
      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 MG
      • Liao J
      • Jo E
      • Alfonso C
      • Ahn MY
      • Peterson MS
      • 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 (Figure 1, Table 2) (
      • Markham A.
      Ponesimod: First Approval.
      ,
      • Bolli MH
      • 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 NS
      • Hinterding K
      • Cooke NG
      • Groenewegen A
      • Vitaliti A
      • Sing T
      • Luttringer O
      • Yang J
      • Gardin A
      • Wang N
      • Crumb Jr, WJ
      • 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 MG
      • Liao J
      • Jo E
      • Alfonso C
      • Ahn MY
      • Peterson MS
      • 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 FL
      • Clemons B
      • Brooks J
      • Brahmachary E
      • Powell R
      • Dedman H
      • Desale HG
      • Timony GA
      • Martinborough E
      • Rosen H
      • Roberts E
      • Boehm MF
      • Peach RJ.
      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 (Figure 1, Table 2) and do not require the action of phosphorylating S1P kinases for activity (
      • Liu H
      • Sugiura M
      • Nava VE
      • Edsall LC
      • 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 AH
      • Sheasley-O'neill SL
      • Morris MA
      • Setiady Y
      • Zhu R
      • Zigler MA
      • Burcin TL
      • Ley K
      • Tung KS
      • Engelhard VH
      • Macdonald TL
      • Pearson-White S
      • Lynch KR
      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 AL
      • 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 JQ
      • Southworth H
      • Spencer CM
      • Cree BAC
      • Zamvil SS.
      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 MP
      • 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 MA
      • 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 JA
      • 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 AB
      • Braune S
      • Stahmann A
      • Middleton R
      • Salter A
      • Fox RJ
      • van der Walt A
      • Butzkueven H
      • Alroughani R
      • Ozakbas S
      • Rojas JI
      • van der Mei I
      • Nag N
      • Ivanov R
      • Sciascia do Olival G
      • Dias AE
      • Magyari M
      • Brum D
      • Mendes MF
      • Alonso RN
      • Nicholas RS
      • Bauer J
      • Chertcoff AS
      • 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
      • Campbell Cree BA
      • Greenberg BM
      • Kundu U
      • Hach T
      • DeLasHeras V
      • Ward BJ
      • 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 BAC
      • Greenberg BM
      • DeLasHeras V
      • Ward BJ.
      COVID-19 outcomes in fingolimod- or siponimod-treated patients: clinical trial and post marketing cases P726.
      *), (

      81.Cree BA, Selmaj KW, Steinman L, Comi G, Bar-Or A, Arnold DL, Hartung HP, Montal X, Havrdova EK, Desai H, Sheffield JK, Minton N, Cheng CY, Silva D, Kappos L, Cohen JA. 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 JG
      • Schwab SR.
      Sphingosine-1-Phosphate and Lymphocyte Egress from Lymphoid Organs.
      ,
      • Bigaud M
      • Nuesslein-Hildesheim B
      • Tran TTT
      • 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 RL
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ,
      • Jurcevic S
      • Juif PE
      • 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 JQ
      • Southworth H
      • Spencer CM
      • Cree BAC
      • Zamvil SS.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ,
      • Cyster JG
      • Schwab SR.
      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 GJ
      • Card D
      • Keohane C
      • Rosenbach M
      • Hale J
      • Lynch CL
      • Rupprecht K
      • Parsons W
      • Rosen H.
      Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
      ,
      • Matloubian M
      • Lo CG
      • Cinamon G
      • Lesneski MJ
      • Xu Y
      • Brinkmann V
      • Allende ML
      • Proia RL
      • Cyster JG.
      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 SF
      • Obermeier B
      • Cotleur A
      • Love A
      • Takeshita Y
      • Sano Y
      • Kanda T
      • Ransohoff RM.
      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 JW
      • Gardell SE
      • Herr DR
      • Rivera R
      • Lee CW
      • Noguchi K
      • Teo ST
      • Yung YC
      • 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 PG
      • Dekker N
      • Witte ME
      • Lopes-Pinheiro MA
      • van het Hof B
      • Kooij G
      • Reijerkerk A
      • Dijkstra C
      • van van der Valk P
      • van Horssen J
      • de Vries HE.
      Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes.
      ,
      • Spampinato SF
      • Merlo S
      • Costantino G
      • Sano Y
      • Kanda T
      • Sortino MA.
      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 RL
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ,
      • Jurcevic S
      • Juif PE
      • 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 JQ
      • Southworth H
      • Spencer CM
      • Cree BAC
      • Zamvil SS.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ,
      • Lu E
      • Cyster JG.
      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 RL
      • 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 defense against pathogens (
      • Mehling M
      • Brinkmann V
      • Antel J
      • Bar-Or A
      • Goebels N
      • Vedrine C
      • Kristofic C
      • Kuhle J
      • Lindberg RL
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ,
      • Jurcevic S
      • Juif PE
      • 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 JQ
      • Southworth H
      • Spencer CM
      • Cree BAC
      • Zamvil SS.
      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 RL
      • Kappos L.
      FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
      ,
      • Jurcevic S
      • Juif PE
      • 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 TA
      • Lapierre Y
      • Bar-Or A
      • Antel JP.
      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 KM
      • Gocke AR
      • Allie R
      • Ntranos A
      • Grishkan IV
      • Pardo C
      • Calabresi PA
      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 ZY
      • 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 JM
      • Sanderson NSR.
      Mass Cytometry of CSF Identifies an MS-Associated B-cell Population.
      ,
      • Kemmerer CL
      • Pernpeintner V
      • Ruschil C
      • Abdelhak A
      • Scholl M
      • Ziemann U
      • Krumbholz M
      • Hemmer B
      • Kowarik MC.
      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 MC
      • Astling D
      • Lepennetier G
      • Ritchie A
      • Hemmer B
      • Owens GP
      • Bennett JL.
      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 AS
      • Schmierer K
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ,
      • Kemmerer CL
      • Pernpeintner V
      • Ruschil C
      • Abdelhak A
      • Scholl M
      • Ziemann U
      • Krumbholz M
      • Hemmer B
      • Kowarik MC.
      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 AS
      • Schmierer K
      • Giovannoni G.
      The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
      ,
      • Baker D
      • Roberts CAK
      • Pryce G
      • Kang AS
      • Marta M
      • Reyes S
      • Schmierer K
      • Giovannoni G
      • Amor S
      COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.
      ,
      • Sormani MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Cocco E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Pizzorno M
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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 (Figure 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 JS
      • O'Halloran JA
      • Kalaidina E
      • Kim W
      • Schmitz AJ
      • Zhou JQ
      • Lei T
      • Thapa M
      • Chen RE
      • Case JB
      • Amanat F
      • Rauseo AM
      • Haile A
      • Xie X
      • Klebert MK
      • Suessen T
      • Middleton WD
      • Shi PY
      • Krammer F
      • Teefey SA
      • Diamond MS
      • Presti RM
      • Ellebedy AH.
      SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses.
      ,
      • Kim W
      • Zhou JQ
      • Horvath SC
      • Schmitz AJ
      • Sturtz AJ
      • Lei T
      • Liu Z
      • Kalaidina E
      • Thapa M
      • Alsoussi WB
      • Haile A
      • Klebert MK
      • Suessen T
      • Parra-Rodriguez L
      • Mudd PA
      • Whelan SPJ
      • Middleton WD
      • Teefey SA
      • Pusic I
      • O'Halloran JA
      • Presti RM
      • Turner JS
      • Ellebedy AH
      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 JG.
      G-protein coupled receptors and ligands that organize humoral immune responses.
      ,
      • Cinamon G
      • Zachariah MA
      • Lam OM
      • Foss Jr, FW
      • Cyster JG.
      Follicular shuttling of marginal zone B cells facilitates antigen transport.
      ,
      • Allende ML
      • Tuymetova G
      • Lee BG
      • Bonifacino E
      • Wu YP
      • Proia RL.
      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 GY
      • Dutt M
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ).
      Figure 2
      Figure 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 GY
      • 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) (
      • Rauser B
      • Ziemssen T
      • Groth M
      • Bopp T
      AMA-VACC: Clinical trial assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod treated patients with secondary progressive multiple sclerosis (P1-1.virtual).
      *), (
      • Siddiqui G
      • Maloni H
      • Nava VE.
      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 MA
      • 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 SR
      • Fox RJ
      • Cruz LA
      • 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=203) (
      • 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 BAC
      • Maddux R
      • Bar-Or A
      • Hartung HP
      • Kaur A
      • Brown E
      • Hu S
      • Sheffield JK
      • 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) & subgroupSARS-CoV-2 Assay(Source)T cell Response assessedReference
      Fingolimod160/220 (72.7%) Varied

      152/198 (76.8%) mRNA

      20/37 (54.1%) mRNA

      11/18 (61.1%) Varied

      n=86 (27.9%) mRNA
      Multiple



      ECLIA (Abbott)

      Multiple

      ELISA (DiaSorin)

      Yes



      Yes

      No

      Yes
      13



      107

      108

      112
      Indicates that the public domain information may not have been peer-reviewed.
      Siponimod15/21 (71.4%) mRNA

      1/1 (100%) mRNA

      11/13 (84.6%) Varied

      3/3 (100%) mRNA

      7/8 (87.5%) Varied

      4/5 (80.0%) mRNA
      Neutralization assay

      ECLIA (Roche)

      ECLIA (Roche)

      ECLIA (Abbott)

      Multiple

      SARS-CoV IgG
      Yes

      No

      No

      No

      No

      No
      67
      Indicates that the public domain information may not have been peer-reviewed.


      105

      106

      107

      108

      109
      Indicates that the public domain information may not have been peer-reviewed.
      Ozanimod3/3 (100%) Varied

      30/30 (100%) Varied

      137/148 (92.6%) Varied

      39/39 (100%) Exposed

      98/109 (89.9%) Naïve

      80/80 (100%) mRNA

      n=22 (84.2%) mRNA
      Multiple

      ECLIA (Roche)

      ECLIA (Roche)







      ELISA (DiaSorin)
      No

      Yes

      No







      Yes
      108

      110
      Indicates that the public domain information may not have been peer-reviewed.


      111
      Indicates that the public domain information may not have been peer-reviewed.








      112
      Indicates that the public domain information may not have been peer-reviewed.
      Ponesimod89/103 (86.4%) Varied

      11/11 (100%) Exposed

      33/38 (86.8%) Naïve

      29/32 (90.6%) mRNA
      ELISA (Nexelis)





      No





      113
      Indicates that the public domain information may not have been peer-reviewed.






      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 electrochemiluminescent 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 GY
      • Dutt M
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ,
      • Rauser B
      • Ziemssen T
      • Groth M
      • Bopp T
      AMA-VACC: Clinical trial assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod treated patients with secondary progressive multiple sclerosis (P1-1.virtual).
      *), (
      • Siddiqui G
      • Maloni H
      • Nava VE.
      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 MA
      • 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 SR
      • Fox RJ
      • Cruz LA
      • 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 BAC
      • Maddux R
      • Bar-Or A
      • Hartung HP
      • Kaur A
      • Brown E
      • Hu S
      • Sheffield JK
      • 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 (Figure 2), contribute to lower antibody titres following vaccination, as suggested by the underlying biology.
      Consistent with other studies (
      • Khoury DS
      • Cromer D
      • Reynaldi A
      • Schlub TE
      • Wheatley AK
      • Juno JA
      • Subbarao K
      • Kent SJ
      • Triccas JA
      • Davenport MP.
      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 DS
      • Cromer D
      • Reynaldi A
      • Schlub TE
      • Wheatley AK
      • Juno JA
      • Subbarao K
      • Kent SJ
      • Triccas JA
      • Davenport MP.
      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 GY
      • Dutt M
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ,
      • Tallantyre EC
      • Vickaryous N
      • Anderson V
      • Asardag AN
      • Baker D
      • Bestwick J
      • Bramhall K
      • Chance R
      • Evangelou N
      • George K
      • Giovannoni G
      • Godkin A
      • Grant L
      • Harding KE
      • Hibbert A
      • Ingram G
      • Jones M
      • Kang AS
      • Loveless S
      • Moat SJ
      • Robertson NP
      • Schmierer K
      • Scurr MJ
      • Shah SN
      • 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 BAC
      • Maddux R
      • Bar-Or A
      • Hartung HP
      • Kaur A
      • Brown E
      • Hu S
      • Sheffield JK
      • 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 BAC
      • Maddux R
      • Bar-Or A
      • Hartung HP
      • Kaur A
      • Brown E
      • Hu S
      • Sheffield JK
      • 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 MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Cocco E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Pizzorno M
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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 KS
      • 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 MK.
      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 EC
      • Vickaryous N
      • Anderson V
      • Asardag AN
      • Baker D
      • Bestwick J
      • Bramhall K
      • Chance R
      • Evangelou N
      • George K
      • Giovannoni G
      • Godkin A
      • Grant L
      • Harding KE
      • Hibbert A
      • Ingram G
      • Jones M
      • Kang AS
      • Loveless S
      • Moat SJ
      • Robertson NP
      • Schmierer K
      • Scurr MJ
      • Shah SN
      • Simmons J
      • Upcott M
      • Willis M
      • Jolles S
      • Dobson R.
      COVID-19 Vaccine Response in People with Multiple Sclerosis.
      ,
      • Tallantyre EC
      • Scurr MJ
      • Vickaryous N
      • Richards A
      • Anderson V
      • Baker D
      • Chance R
      • Evangelou N
      • George K
      • Giovannoni G
      • Harding KE
      • Hibbert A
      • Ingram G
      • Jolles S
      • Jones M
      • Kang AS
      • Loveless S
      • Moat SJ
      • Robertson NP
      • 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 HM
      • Tran TT
      • Holmøy T
      • Vaage JT
      • Lund-Johansen F
      • Nygaard GO.
      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 BAC
      • Maddux R
      • Bar-Or A
      • Hartung HP
      • Kaur A
      • Brown E
      • Hu S
      • Sheffield JK
      • 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 MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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.
      ,
      • Pitzalis M
      • Idda ML
      • Lodde V
      • Loizedda A
      • Lobina M
      • Zoledziewska M
      • Virdis F
      • Delogu G
      • Pirinu F
      • Marini MG
      • 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 IR
      • 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 MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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 20U/ml (
      • Sormani MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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 26.7U/ml (n=71) was reported in infection-naïve, tozinameran-vaccinated individuals (
      • Pitzalis M
      • Idda ML
      • Lodde V
      • Loizedda A
      • Lobina M
      • Zoledziewska M
      • Virdis F
      • Delogu G
      • Pirinu F
      • Marini MG
      • 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 IR
      • 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 >133U/ml occurred in fingolimod-treated individuals (
      • Pitzalis M
      • Idda ML
      • Lodde V
      • Loizedda A
      • Lobina M
      • Zoledziewska M
      • Virdis F
      • Delogu G
      • Pirinu F
      • Marini MG
      • 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 IR
      • 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 BAC
      • Maddux R
      • Bar-Or A
      • Hartung HP
      • Kaur A
      • Brown E
      • Hu S
      • Sheffield JK
      • 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 GY
      • 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 MA
      • 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 GY
      • Dutt M
      • Tyor W.
      Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.
      ,
      • Tallantyre EC
      • Vickaryous N
      • Anderson V
      • Asardag AN
      • Baker D
      • Bestwick J
      • Bramhall K
      • Chance R
      • Evangelou N
      • George K
      • Giovannoni G
      • Godkin A
      • Grant L
      • Harding KE
      • Hibbert A
      • Ingram G
      • Jones M
      • Kang AS
      • Loveless S
      • Moat SJ
      • Robertson NP
      • Schmierer K
      • Scurr MJ
      • Shah SN
      • 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 LE
      • 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 AS
      • Ravussin A
      • König M
      • Øverås MH
      • Solum S
      • Fadum Kjønstad I
      • Chopra A
      • Holmøy T
      • Harbo HF
      • Watterdal S.Syversen
      • Kaasen Jørgensenn K
      • August Høgestøl F
      • Torgils Vaage J
      • Celius EG
      • Lund-Johansen F
      • Munthe LA
      • 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 (
      • Rauser B
      • Ziemssen T
      • Groth M
      • Bopp T
      AMA-VACC: Clinical trial assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod treated patients with secondary progressive multiple sclerosis (P1-1.virtual).
      *), (
      • Kantor D.
      SARS-CoV-2 vaccine response in RMS patients treated with ozanimod and other DMTs P13-4.008.
      *), (
      • 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.
      *). However, as memory T and B cell recall responses require stimulation and are maintained even after antibody titres are diminished (
      • Tallantyre EC
      • Vickaryous N
      • Anderson V
      • Asardag AN
      • Baker D
      • Bestwick J
      • Bramhall K
      • Chance R
      • Evangelou N
      • George K
      • Giovannoni G
      • Godkin A
      • Grant L
      • Harding KE
      • Hibbert A
      • Ingram G
      • Jones M
      • Kang AS
      • Loveless S
      • Moat SJ
      • Robertson NP
      • Schmierer K
      • Scurr MJ
      • Shah SN
      • Simmons J
      • Upcott M
      • Willis M
      • Jolles S
      • Dobson R.
      COVID-19 Vaccine Response in People with Multiple Sclerosis.
      ,
      • König M
      • Torgauten HM
      • Tran TT
      • Holmøy T
      • Vaage JT
      • Lund-Johansen F
      • Nygaard GO.
      Immunogenicity and Safety of a Third SARS-CoV-2 Vaccine Dose in Patients With Multiple Sclerosis and Weak Immune Response After COVID-19 Vaccination.
      ,
      • Moore T
      • Hossain R
      • Doores KJ
      • Shankar-Hari M
      • Fear DJ.
      SARS-CoV-2-specific memory B cell responses are maintained after recovery from natural infection and postvaccination.
      ), the threshold level needed for immune protection requires further study and may vary with time, notably related to the changing circulating SARS-CoV-2 variant of concern, as seen with antibody protection from infection (
      • Khoury DS
      • Cromer D
      • Reynaldi A
      • Schlub TE
      • Wheatley AK
      • Juno JA
      • Subbarao K
      • Kent SJ
      • Triccas JA
      • Davenport MP.
      Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.
      ,
      • Sormani MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Cocco E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Pizzorno M
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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 KS
      • 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.
      ).

      4.2 Influence of non-sphingosine-1-phopshate 1 receptors controlling antibody responses

      None of the current S1PR modulators target S1PR2 (Table 2) and this may be beneficial for vaccine responses as SP1R2 and the CXCR5 chemokine regulate the localization of follicular helper T cells into the B cell follicles to promote antibody responses and are particularly important for germinal centre reactions, where they can function to help antibody responses to novel antigens, through production of cytokines and co-stimulatory molecules (
      • Moriyama S
      • Takahashi N
      • Green JA
      • Hori S
      • Kubo M
      • Cyster JG
      • Okada T.
      Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers.
      ,
      • Cohan SL
      • Baumjohann D
      • Fazilleau N.
      Antigen-dependent multistep differentiation of T follicular helper cells and its role in SARS-CoV-2 infection and vaccination.
      ). Furthermore, S1PR2 is expressed by B cells within follicles (Figure 2) and this regulates entry into a plasma cell or recycling germinal centre cell fate and maintains the homeostasis of germinal centre B cells (
      • Cattoretti G
      • Mandelbaum J
      • Lee N
      • Chaves AH
      • Mahler AM
      • Chadburn A
      • et al.
      Targeted disruption of the S1P 2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation.
      ,
      • Green JA
      • Suzuki K
      • Cho B
      • Willison LD
      • Palmer D
      • Allen CD
      • Schmidt TH
      • Xu Y
      • Proia RL
      • Coughlin SR
      • Cyster JG.
      The sphingosine 1-phosphate receptor S1P₂ maintains the homeostasis of germinal center B cells and promotes niche confinement.
      ,
      • Green JA
      • Cyster JG.
      S1PR2 links germinal center confinement and growth regulation.
      ,
      • Ise W
      • Fujii K
      • Shiroguchi K
      • Ito A
      • Kometani K
      • Takeda K
      • Kawakami E
      • Yamashita K
      • Suzuki K
      • Okada T
      • Kurosaki T.
      T Follicular Helper Cell-Germinal Center B cell interaction strength regulates entry into plasma cell or recycling germinal center cell fate.
      ,
      • Al-Kawaaz M
      • Sanchez T
      • Kluk MJ.
      Evaluation of S1PR1, pSTAT3, S1PR2, FOXP1 expression in aggressive, mature B cell lymphomas.
      ). As such, S1PR2 may inhibit some S1PR1-mediated functions (
      • Sic H
      • Kraus H
      • Madl J
      • Flittner KA
      • von Münchow AL
      • Pieper K
      • Rizzi M
      • Kienzler AK
      • Ayata K
      • Rauer S
      • Kleuser B
      • Salzer U
      • Burger M
      • Zirlik K
      • Lougaris V
      • Plebani A
      • Römer W
      • Loeffler C
      • Scaramuzza S
      • Villa A
      • Noguchi E
      • Grimbacher B
      • Eibel H.
      Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis.
      ).
      In contrast, it is also possible to speculate that potential differences between fingolimod and the other S1P modulators could occur due to an activity on S1PR3. Indeed, it has been suggested that S1PR3 controls B cell function (
      • Cinamon G
      • Zachariah MA
      • Lam OM
      • Foss Jr, FW
      • Cyster JG.
      Follicular shuttling of marginal zone B cells facilitates antigen transport.
      ,
      • Tedford K
      • Steiner M
      • Koshutin S
      • Richter K
      • Tech L
      • Eggers Y
      • Jansing I
      • Schilling K
      • Hauser AE
      • Korthals M
      • Fischer KD.
      The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling.
      ,
      • Donovan EE
      • Pelanda R
      • Torres RM.
      S1P3 confers differential S1P-induced migration by autoreactive and non-autoreactive immature B cells and is required for normal B-cell development.
      ). Notably, this receptor has been associated with the development of progenitor cells; positioning of immature B cells within bone marrow sinusoids and migration of B cells within the bone marrow and lymphoid tissues (
      • Donovan EE
      • Pelanda R
      • Torres RM.
      S1P3 confers differential S1P-induced migration by autoreactive and non-autoreactive immature B cells and is required for normal B-cell development.
      ,
      • Muppidi JR
      • Lu E
      • Cyster JG.
      The G protein-coupled receptor P2RY8 and follicular dendritic cells promote germinal center confinement of B cells, whereas S1PR3 can contribute to their dissemination.
      ,
      • Ogle ME
      • Olingy CE
      • Awojoodu AO
      • Das A
      • Ortiz RA
      • Cheung HY
      • Botchwey EA.
      Sphingosine-1-phosphate receptor-3 supports hematopoietic stem and progenitor cell residence within the bone marrow niche.
      ). Importantly, it is involved in B cell capture of antigens in the marginal zones and shuttling to B cell follicles for the development of antibodies (
      • Cinamon G
      • Zachariah MA
      • Lam OM
      • Foss Jr, FW
      • Cyster JG.
      Follicular shuttling of marginal zone B cells facilitates antigen transport.
      ,
      • Tedford K
      • Steiner M
      • Koshutin S
      • Richter K
      • Tech L
      • Eggers Y
      • Jansing I
      • Schilling K
      • Hauser AE
      • Korthals M
      • Fischer KD.
      The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling.
      ). However, this view may only reflect the case in rodents, as there is a paucity of evidence to suggest an S1PR3-mediated B cell activity in humans. As such, there may be subtle differences in the migration cues between rodent and humans (
      • Park SM
      • Brooks AE
      • Chen CJ
      • Sheppard HM
      • Loef EJ
      • McIntosh JD
      • Angel CE
      • Mansell CJ
      • Bartlett A
      • Cebon J
      • Birch NP
      • Dunbar PR.
      Migratory cues controlling B-lymphocyte trafficking in human lymph nodes.
      ). Importantly, whilst mouse B cells express S1PR3 (
      • Donovan EE
      • Pelanda R
      • Torres RM.
      S1P3 confers differential S1P-induced migration by autoreactive and non-autoreactive immature B cells and is required for normal B-cell development.
      ,
      • Wu C
      • Orozco C
      • Boyer J
      • Leglise M
      • Goodale J
      • Batalov S
      • Hodge CL
      • Haase J
      • Janes J
      • Huss 3rd, JW
      • Su AI.
      BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources.
      ) it appears that human B cells express limited S1PR3 mRNA (
      • Wu C
      • Orozco C
      • Boyer J
      • Leglise M
      • Goodale J
      • Batalov S
      • Hodge CL
      • Haase J
      • Janes J
      • Huss 3rd, JW
      • Su AI.
      BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources.
      ,
      • Kassambara A
      • Rème T
      • Jourdan M
      • Fest T
      • Hose D
      • Tarte K
      • Klein B
      GenomicScape: an easy-to-use web tool for gene expression data analysis. Application to investigate the molecular events in the differentiation of B cells into plasma cells.
      ) (Figure 2). This may have parallels with the cardiac side-effect activity that was originally attributed to S1PR3, based on rodent studies (
      • Gergely P
      • Nuesslein-Hildesheim B
      • Guerini D
      • Brinkmann V
      • Traebert M
      • Bruns C
      • Pan S
      • Gray NS
      • Hinterding K
      • Cooke NG
      • Groenewegen A
      • Vitaliti A
      • Sing T
      • Luttringer O
      • Yang J
      • Gardin A
      • Wang N
      • Crumb Jr, WJ
      • 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 MG
      • Liao J
      • Jo E
      • Alfonso C
      • Ahn MY
      • Peterson MS
      • 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.
      ). It is now evident that these issues are mediated by S1PR1 in humans (
      • Gergely P
      • Nuesslein-Hildesheim B
      • Guerini D
      • Brinkmann V
      • Traebert M
      • Bruns C
      • Pan S
      • Gray NS
      • Hinterding K
      • Cooke NG
      • Groenewegen A
      • Vitaliti A
      • Sing T
      • Luttringer O
      • Yang J
      • Gardin A
      • Wang N
      • Crumb Jr, WJ
      • 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.
      ). As such all approved S1P modulators, including those with no/limited S1PR3 activity can induce cardiac arrhythmias (
      • Al-Salama ZT.
      • Siponimod
      ,
      • Lamb YN.
      Ozanimod: First Approval.
      ,
      • Markham A.
      Ponesimod: First Approval.
      ,
      • Scott LJ.
      Fingolimod: a review of its use in the management of relapsing-remitting multiple sclerosis.
      ). However, S1PR3 can be pathologically regulated within lymphoid tissues and may have some element to play in B cell development, notably as it has been suggested that S1PR3 contributes to vascular and dendritic cell function within B cell areas (
      • Muppidi JR
      • Lu E
      • Cyster JG.
      The G protein-coupled receptor P2RY8 and follicular dendritic cells promote germinal center confinement of B cells, whereas S1PR3 can contribute to their dissemination.
      ,
      • Girkontaite I
      • Sakk V
      • Wagner M
      • Borggrefe T
      • Tedford K
      • Chun J
      • Fischer KD.
      The sphingosine-1-phosphate (S1P) lysophospholipid receptor S1P3 regulates MAdCAM-1+ endothelial cells in splenic marginal sinus organization.
      ,
      • Middle S
      • Coupland SE
      • Taktak A
      • Kidgell V
      • Slupsky JR
      • Pettitt AR
      • Till KJ.
      Immunohistochemical analysis indicates that the anatomical location of B-cell non-Hodgkin's lymphoma is determined by differentially expressed chemokine receptors, sphingosine-1-phosphate receptors and integrins.
      ,
      • Nussbaum C
      • Bannenberg S
      • Keul P
      • Gräler MH
      • Gonçalves-de-Albuquerque CF
      • Korhonen H
      • von Wnuck Lipinski K
      • Heusch G
      • de Castro Faria Neto HC
      • Rohwedder I
      • Göthert JR
      • Prasad VP
      • Haufe G
      • Lange-Sperandio B
      • Offermanns S
      • Sperandio M
      • Levkau B
      Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin.
      ). As such S1PR3 can control dendritic cell migration into secondary lymphoid tissues and monocyte activity (
      • Maeda Y
      • Matsuyuki H
      • Shimano K
      • Kataoka H
      • Sugahara K
      • Chiba K.
      Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3.
      ,
      • Keul P
      • Lucke S
      • von Wnuck Lipinski K
      • Bode C
      • Gräler M
      • Heusch G
      • Levkau B.
      Sphingosine-1-phosphate receptor 3 promotes recruitment of monocyte/macrophages in inflammation and atherosclerosis.
      ) and may influence the generation of primary immune responses that ultimately lead to a vaccination response (Figure 2).
      Indeed, it is evident that S1PR4 is widely expressed by immune cells subsets (Figure 2), including platelets (
      • Golfier S
      • Kondo S
      • Schulze T
      • Takeuchi T
      • Vassileva G
      • Achtman AH
      • Gräler MH
      • Abbondanzo SJ
      • Wiekowski M
      • Kremmer E
      • Endo Y
      • Lira SA
      • Bacon KB
      • Lipp M.
      Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P4.
      ) (Figure 2) and that S1PR4 modulation may mediate effects on T and B cell migration and may modulate S1PR1 function (
      • Sic H
      • Kraus H
      • Madl J
      • Flittner KA
      • von Münchow AL
      • Pieper K
      • Rizzi M
      • Kienzler AK
      • Ayata K
      • Rauer S
      • Kleuser B
      • Salzer U
      • Burger M
      • Zirlik K
      • Lougaris V
      • Plebani A
      • Römer W
      • Loeffler C
      • Scaramuzza S
      • Villa A
      • Noguchi E
      • Grimbacher B
      • Eibel H.
      Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis.
      ,
      • Wang W
      • Graeler MH
      • Goetzl EJ.
      Type 4 sphingosine 1-phosphate G protein-coupled receptor (S1P4) transduces S1P effects on T cell proliferation and cytokine secretion without signaling migration.
      ,
      • Xiong Y
      • Piao W
      • Brinkman CC
      • Li L
      • Kulinski JM
      • Olivera A
      • Cartier A
      • Hla T
      • Hippen KL
      • Blazar BR
      • Schwab SR
      • Bromberg JS.
      CD4 T cell sphingosine 1-phosphate receptor (S1PR)1 and S1PR4 and endothelial S1PR2 regulate afferent lymphatic migration.
      ,
      • Olesch C
      • Sirait-Fischer E
      • Berkefeld M
      • Fink AF
      • Susen RM
      • Ritter B
      • Michels BE
      • Steinhilber D
      • Greten FR
      • Savai R
      • Takeda K
      • Brüne B
      • Weigert A.
      S1PR4 ablation reduces tumor growth and improves chemotherapy via CD8+ T cell expansion.
      ,
      • Riese J
      • Gromann A
      • Lührs F
      • Kleinwort A
      • Schulze T.
      Sphingosine-1-Phosphate Receptor Type 4 (S1P4) Is Differentially Regulated in Peritoneal B1 B Cells upon TLR4 Stimulation and Facilitates the Egress of Peritoneal B1a B Cells and Subsequent Accumulation of Splenic IRA B Cells under Inflammatory Conditions.
      ), S1pr4-gene deficient mice have normal lymphocyte numbers and regular architecture of secondary lymphoid organs (
      • Schulze T
      • Golfier S
      • Tabeling C
      • Räbel K
      • Gräler MH
      • Witzenrath M
      • Lipp M.
      Sphingosine-1-phospate receptor 4 (S1P₄) deficiency profoundly affects dendritic cell function and TH17-cell differentiation in a murine model.
      ). In contrast, there was a marked impact of S1PR4 depletion on dendritic cell migration and cytokine secretion leading to reduced Th17 T-cell differentiation and inhibition of mouse and human dendritic cell activity (
      • Schulze T
      • Golfier S
      • Tabeling C
      • Räbel K
      • Gräler MH
      • Witzenrath M
      • Lipp M.
      Sphingosine-1-phospate receptor 4 (S1P₄) deficiency profoundly affects dendritic cell function and TH17-cell differentiation in a murine model.
      ,
      • Mosheimer B
      • Mayer G
      • Konwalinka G
      • Heufler C
      • Tiefenthaler M.
      The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells.
      ,
      • Olesch C
      • Ringel C
      • Brüne B
      • Weigert A.
      Beyond immune cell migration: the emerging role of the sphingosine-1-phosphate receptor s1pr4 as a modulator of innate immune cell activation.
      ). There is S1PR-mediated control of dendritic (Langerhans) cell migration from the skin (
      • Bock S
      • Pfalzgraff A
      • Weindl G.
      Sphingosine 1-phospate differentially modulates maturation and function of human Langerhans-like cells.
      ). This could impact antigen-presenting cell function in vaccine-induced responses and may affect progenitor development in the bone marrow that limit the occurrence of dendritic cells (
      • Olesch C
      • Ringel C
      • Brüne B
      • Weigert A.
      Beyond immune cell migration: the emerging role of the sphingosine-1-phosphate receptor s1pr4 as a modulator of innate immune cell activation.
      ,
      • Dillmann C
      • Mora J
      • Olesch C
      • Brüne B
      • Weigert A.
      S1PR4 is required for plasmacytoid dendritic cell differentiation.
      ). Furthermore, S1PR4 is required for plasmacytoid dendritic cell differentiation (
      • Dillmann C
      • Mora J
      • Olesch C
      • Brüne B
      • Weigert A.
      S1PR4 is required for plasmacytoid dendritic cell differentiation.
      ). Plasmacytoid dendritic cells secrete high levels of interleukin-6 and type I interferons in response to infection, which are protective against the SARS-CoV-2 virus and can help induce the differentiation of B cells into IgG-secreting plasma cells (
      • Le Bon A
      • Schiavoni G
      • D'Agostino G
      • Gresser I
      • Belardelli F
      • Tough DF
      Type interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo.
      ,
      • Jego G
      • Palucka AK
      • Blanck JP
      • Chalouni C
      • Pascual V
      • Banchereau J.
      Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6.
      ,
      • Poeck H
      • Wagner M
      • Battiany J
      • Rothenfusser S
      • Wellisch D
      • Hornung V
      • Jahrsdorfer B
      • Giese T
      • Endres S
      • Hartmann G.
      Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help.
      ). The innate immune system and endothelial express the S1P kinases, notably SPHK1 and can respond to fingolimod (
      • Schwiebs A
      • Friesen O
      • Katzy E
      • Ferreirós N
      • Pfeilschifter JM
      • Radeke HH.
      Activation-Induced Cell Death of Dendritic Cells Is Dependent on Sphingosine Kinase 1.
      ,
      • Mohammed S
      • Vineetha NS
      • James S
      • Aparna JS
      • Lankadasari MB
      • Allegood JC
      • Li QZ
      • Spiegel S
      • Harikumar KB.
      Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus.
      ). However, it is important to note that the affinity of fingolimod for S1PR4 may be low in some functional assays (Table 2) and therefore differences between this and other agents may only be incremental. Likewise, it is possible that differences between fingolimod and other agents could relate to the requirement for phosphorylation that may vary due to the potential differential expression of SPKH1 and SPKH2 in tissues influencing fingolimod activity (
      • Brinkmann V
      • Davis MD
      • Heise CE
      • Albert R
      • Cottens S
      • Hof R
      • Bruns C
      • Prieschl E
      • Baumruker T
      • Hiestand P
      • Foster CA
      • Zollinger M
      • Lynch KR.
      The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
      ,
      • Liu H
      • Sugiura M
      • Nava VE
      • Edsall LC
      • Kono K
      • Poulton S
      • et al.
      Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform.
      )
      The potential differences observed between seroconversion after infection or vaccination during fingolimod use may simply reflect variability between studies and it is important to note in both cases the level of response is often diminished compared to untreated individuals. However, whilst vaccination is induced via the skin, natural infection with SARS-COV-2 occurs via the pulmonary and mucosal surfaces over time and so the range of antigen-presenting cells and lymphoid tissues involved may be broader and may account for potentially better seroconversion in these immunosuppressed people (
      • Poeck H
      • Wagner M
      • Battiany J
      • Rothenfusser S
      • Wellisch D
      • Hornung V
      • Jahrsdorfer B
      • Giese T
      • Endres S
      • Hartmann G.
      Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help.
      ,
      • Schwiebs A
      • Friesen O
      • Katzy E
      • Ferreirós N
      • Pfeilschifter JM
      • Radeke HH.
      Activation-Induced Cell Death of Dendritic Cells Is Dependent on Sphingosine Kinase 1.
      ,
      • Mohammed S
      • Vineetha NS
      • James S
      • Aparna JS
      • Lankadasari MB
      • Allegood JC
      • Li QZ
      • Spiegel S
      • Harikumar KB.
      Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus.
      ). We hypothesise that the apparent, subtle, differences between fingolimod and the newer generation S1PR modulators are most likely due to differences on SIPR3 and notably SP1R4 modulation on the germinal centre formation and function, which are critical for neoantigen antibody responses (Figure 3).
      Figure 3
      Figure 3The germinal centre reaction to generate vaccine responses. Hypothetical activity of S1PR in generating vaccine-induced antibody responses. This involves S1PR4-related migration of dendritic/Langerhans cells from blood to tissues and from sites of inflammation to lymphoid tissues. T cells are activated, expanded and differentiated prior to recirculation to lymphoid (CD62L+) or inflamed tissue (CD44+, CD49d). CD4+ follicular T-helper cells migrate into and stay in B-cell follicles to support B-cell development and maturation and the formation of germinal centre cells. Naïve B cells capture antigens from the marginal zone become activated and differentiate to memory B cells, plasmablasts and long-lived plasma cells that reside in the bone marrow and secrete antibody. Short-lived plasma cells may be formed from extra-germinal centre B-cell areas. Created with Biorender.com

      5. Influence of SARS-CoV-2 antiviral agents on S1PR modulators

      5.1 Anti-viral antibodies

      From SARS-CoV-2 vaccination have the potential to provide protection from infection and disease-related morbidity, but it is not infallible (
      • Sormani MP
      • 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 ML
      • Cordioli C
      • Landi D
      • Clerico M
      • Signoriello E
      • Frau J
      • Ferrò MT
      • Di Sapio A
      • Pasquali L
      • Ulivelli M
      • Marinelli F
      • Callari G
      • Iodice R
      • Liberatore G
      • Caleri F
      • Repice AM
      • Cordera S
      • Battaglia MA
      • 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.
      ,
      • Tuekprakhon A
      • Nutalai R
      • Dijokaite-Guraliuc A
      • Zhou D
      • Ginn HM
      • Selvaraj M
      • Liu C
      • Mentzer AJ
      • Supasa P
      • Duyvesteyn HME
      • Das R
      • Skelly D
      • Ritter TG
      • Amini A
      • Bibi S
      • Adele S
      • Johnson SA
      • Constantinides B
      • Webster H
      • Temperton N
      • Klenerman P
      • Barnes E
      • Dunachie SJ
      • Crook D
      • Pollard AJ
      • Lambe T
      • Goulder P
      • Paterson NG
      • Williams MA
      • Hall DR
      • Fry EE
      • Huo J
      • Mongkolsapaya J
      • Ren J
      • Stuart DI
      • Screaton GR
      OPTIC ConsortiumISARIC4C Consortium
      Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum.
      ,
      • Peng P
      • Deng H
      • Li Z
      • Chen Y
      • Fang L
      • Hu J
      • Wu K
      • Xue J
      • Wang D
      • Liu B
      • Long Q
      • Chen J
      • Wang K
      • Tang N
      • Huang AL.
      Distinct immune responses in the early phase to natural SARS-CoV-2 infection or vaccination.
      ,
      • Cho A
      • Muecksch F
      • Schaefer-Babajew D
      • Wang Z
      • Finkin S
      • Gaebler C
      • Ramos V
      • Cipolla M
      • Mendoza P
      • Agudelo M
      • Bednarski E
      • DaSilva J
      • Shimeliovich I
      • Dizon J
      • Daga M
      • Millard KG
      • Turroja M
      • Schmidt F
      • Zhang F
      • Tanfous TB
      • Jankovic M
      • Oliveria TY
      • Gazumyan A
      • Caskey M
      • Bieniasz PD
      • Hatziioannou T
      • Nussenzweig MC.
      Anti-SARS-CoV-2 receptor-binding domain antibody evolution after mRNA vaccination.
      ,
      • Gazit S
      • Shlezinger R
      • Perez G
      • Lotan R
      • Peretz A
      • Ben-Tov A
      • Herzel E
      • Alapi H
      • Cohen D
      • Muhsen K
      • Chodick G
      • Patalon T.
      SARS-CoV-2 naturally acquired immunity vs. vaccine-induced immunity, reinfections versus breakthrough infections: a retrospective cohort Study.
      ,
      • Antonelli M
      • Penfold RS
      • Merino J
      • Sudre CH
      • Molteni E
      • Berry S
      • Canas LS
      • Graham MS
      • Klaser K
      • Modat M
      • Murray B
      • Kerfoot E
      • Chen L
      • Deng J
      • Österdahl MF
      • Cheetham NJ
      • Drew DA
      • Nguyen LH
      • Pujol JC
      • Hu C
      • Selvachandran S
      • Polidori L
      • May A
      • Wolf J
      • Chan AT
      • Hammers A
      • Duncan EL
      • Spector TD
      • Ourselin S
      • Steves CJ.
      Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study.
      ). This may especially be the case as viral variants have evolved that are relatively resistant to the original SARS-CoV-2 spike-based serology and vaccines (
      • Tuekprakhon A
      • Nutalai R
      • Dijokaite-Guraliuc A
      • Zhou D
      • Ginn HM
      • Selvaraj M
      • Liu C
      • Mentzer AJ
      • Supasa P
      • Duyvesteyn HME
      • Das R
      • Skelly D
      • Ritter TG
      • Amini A
      • Bibi S
      • Adele S
      • Johnson SA
      • Constantinides B
      • Webster H
      • Temperton N
      • Klenerman P
      • Barnes E
      • Dunachie SJ
      • Crook D
      • Pollard AJ
      • Lambe T
      • Goulder P
      • Paterson NG
      • Williams MA
      • Hall DR
      • Fry EE
      • Huo J
      • Mongkolsapaya J
      • Ren J
      • Stuart DI
      • Screaton GR
      OPTIC ConsortiumISARIC4C Consortium
      Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum.
      ,
      • Schiavetti L
      • Barcellini C
      • Lapucci F
      • Tazza M
      • Cellerino E
      • Capello D
      • Franciotta M
      • Inglese Sormani MP
      • Uccelli A
      • Laroni A
      CD19+ B cell numbers predict the increase of anti-SARS CoV2 antibodies in fingolimod-treated and COVID-19-vaccinated patients with multiple sclerosis.
      *), (
      • Planas D
      • Saunders N
      • Maes P
      • Guivel-Benhassine F
      • Planchais C
      • Buchrieser J
      • Bolland WH
      • Porrot F
      • Staropoli I
      • Lemoine F
      • Péré H
      • Veyer D
      • Puech J
      • Rodary J
      • Baele G
      • Dellicour S
      • Raymenants J
      • Gorissen S
      • Geenen C
      • Vanmechelen B
      • Wawina-Bokalanga T
      • Martí-Carreras J
      • Cuypers L
      • Sève A
      • Hocqueloux L
      • Prazuck T
      • Rey FA
      • Simon-Loriere E
      • Bruel T
      • Mouquet H
      • André E
      • Schwartz O.
      Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.
      ,
      • Wang Q
      • Guo Y
      • Iketani S
      • Nair MS
      • Li Z
      • Mohri H
      • Wang M
      • Yu J
      • Bowen AD
      • Chang JY
      • Shah JG
      • Nguyen N
      • Chen Z
      • Meyers K
      • Yin MT
      • Sobieszczyk ME
      • Sheng Z
      • Huang Y
      • Liu L
      • Ho DD.
      Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, & BA.5.
      ). However, blocking the serological responses to infection and/or vaccination in immunosuppressed-individuals have supported the need for effective anti-viral treatments. Monoclonal antibodies often generated from COVID-19 convalescent individuals have shown promise in protecting individuals from infection (
      • Planas D
      • Saunders N
      • Maes P
      • Guivel-Benhassine F
      • Planchais C
      • Buchrieser J
      • Bolland WH
      • Porrot F
      • Staropoli I
      • Lemoine F
      • Péré H
      • Veyer D
      • Puech J
      • Rodary J
      • Baele G
      • Dellicour S
      • Raymenants J
      • Gorissen S
      • Geenen C
      • Vanmechelen B
      • Wawina-Bokalanga T
      • Martí-Carreras J
      • Cuypers L
      • Sève A
      • Hocqueloux L
      • Prazuck T
      • Rey FA
      • Simon-Loriere E
      • Bruel T
      • Mouquet H
      • André E
      • Schwartz O.
      Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.
      ,
      • Wang Q
      • Guo Y
      • Iketani S
      • Nair MS
      • Li Z
      • Mohri H
      • Wang M
      • Yu J
      • Bowen AD
      • Chang JY
      • Shah JG
      • Nguyen N
      • Chen Z
      • Meyers K
      • Yin MT
      • Sobieszczyk ME
      • Sheng Z
      • Huang Y
      • Liu L
      • Ho DD.
      Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, & BA.5.
      ,
      • Focosi D
      • McConnell S
      • Casadevall A
      • Cappello E
      • Valdiserra G
      • Tuccori M.
      Monoclonal antibody therapies against SARS-CoV-2.
      ,
      • Woopen C
      • Konofalska U
      • Akgün K
      • Ziemssen T.
      Case report: Variant-specific pre-exposure prophylaxis of SARS-CoV-2 infection in multiple sclerosis patients lacking vaccination responses.
      ). There, is limited expression of S1PR receptors, except for S1PR4, by polymorphonuclear neutrophils and neutropenia is not typically associated with S1PR modulation and may control egress from inflamed tissues (
      • Harris S
      • Tran JQ
      • Southworth H
      • Spencer CM
      • Cree BAC
      • Zamvil SS.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ,
      • Sehr T
      • Akgün K
      • Haase R
      • Ziemssen T.
      Fingolimod leads to immediate immunological changes within 6 h after first administration.
      ,
      • Mao-Draayer Y
      • Wu Q
      • Wang Q
      • Dowling C
      • Lundy S
      • Fox D.
      Basic immunological profile changes of secondary progressive multiple sclerosis patients treated with BAF312 (Siponimod).
      ). Although fingolimod, siponimod and ozanimod could perhaps influence natural killer (NK) cell function secondary to effects notably on S1P5R, and in the case of fingolimod S1P4R, associated migration (
      • 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 AL
      • 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.
      ). Again, peripheral NK depletion is modest following S1PR modulation (
      • Harris S
      • Tran JQ
      • Southworth H
      • Spencer CM
      • Cree BAC
      • Zamvil SS.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ,
      • Mehling M
      • Burgener AV
      • Brinkmann V
      • Bantug GR
      • Dimeloe S
      • Hoenger G
      • Kappos L
      • Hess C.
      Tissue Distribution Dynamics of Human NK Cells Inferred from Peripheral Blood Depletion Kinetics after Sphingosine-1-Phosphate Receptor Blockade.
      ,
      • Michel T
      • Poli A
      • Cuapio A
      • Briquemont B
      • Iserentant G
      • Ollert M
      • Zimmer J.
      Human CD56bright NK Cells: An Update.
      ). This probably reflects a more limited activity on the CD16+, CD56dim NK cell subset that are dominant in the periphery and are important for antibody-mediated cytotoxicity (
      • Harris S
      • Tran JQ
      • Southworth H
      • Spencer CM
      • Cree BAC
      • Zamvil SS.
      Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.
      ,
      • Mao-Draayer Y
      • Wu Q
      • Wang Q
      • Dowling C
      • Lundy S
      • Fox D.
      Basic immunological profile changes of secondary progressive multiple sclerosis patients treated with BAF312 (Siponimod).
      ,
      • Mehling M
      • Burgener AV
      • Brinkmann V
      • Bantug GR
      • Dimeloe S
      • Hoenger G
      • Kappos L
      • Hess C.
      Tissue Distribution Dynamics of Human NK Cells Inferred from Peripheral Blood Depletion Kinetics after Sphingosine-1-Phosphate Receptor Blockade.
      ). There is therefore limited reason to believe that S1PR would directly influence viral activity via antibodies or a direct effect on viral activity. However, poor viral elimination in SARS-CoV-2 neutralizing antibody-treated and immunosuppressed people can support the selection of immune escape variants that can render SARS-CoV-2-specific neutralizing antibodies such as casirivimab/imdevimab, tixagevimab/cilgavimab and sotrovimab to become rather ineffective as the SARS-CoV-2 virus evolves (
      • Shrestha LB
      • Foster C
      • Rawlinson W
      • Tedla N
      • Bull RA.
      Evolution of the SARS-CoV-2 omicron variants BA.1 to BA.5: Implications for immune escape and transmission.
      ,
      • Scherer EM
      • Babiker A
      • Adelman MW
      • Allman B
      • Key A
      • Kleinhenz JM
      • Langsjoen RM
      • Nguyen PV
      • Onyechi I
      • Sherman JD
      • Simon TW
      • Soloff H
      • Tarabay J
      • Varkey J
      • Webster AS
      • Weiskopf D
      • Weissman DB
      • Xu Y
      • Waggoner JJ
      • Koelle K
      • Rouphael N
      • Pouch SM
      • Piantadosi A.
      SARS-CoV-2 evolution and immune escape in immunocompromised patients.
      ,
      • Ohashi H
      • Hishiki T
      • Akazawa D
      • Kim KS
      • 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.
      ,
      • Planas D
      • Saunders N
      • Maes P
      • Guivel-Benhassine F
      • Planchais C
      • Buchrieser J
      • Bolland WH
      • Porrot F
      • Staropoli I
      • Lemoine F
      • Péré H
      • Veyer D
      • Puech J
      • Rodary J
      • Baele G
      • Dellicour S
      • Raymenants J
      • Gorissen S
      • Geenen C
      • Vanmechelen B
      • Wawina-Bokalanga T
      • Martí-Carreras J
      • Cuypers L
      • Sève A
      • Hocqueloux L
      • Prazuck T
      • Rey FA
      • Simon-Loriere E
      • Bruel T
      • Mouquet H
      • André E
      • Schwartz O.
      Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.
      ,
      • Wang Q
      • Guo Y
      • Iketani S
      • Nair MS
      • Li Z
      • Mohri H
      • Wang M
      • Yu J
      • Bowen AD
      • Chang JY
      • Shah JG
      • Nguyen N
      • Chen Z
      • Meyers K
      • Yin MT
      • Sobieszczyk ME
      • Sheng Z
      • Huang Y
      • Liu L
      • Ho DD.
      Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, & BA.5.
      ,
      • Woopen C
      • Konofalska U
      • Akgün K
      • Ziemssen T.
      Case report: Variant-specific pre-exposure prophylaxis of SARS-CoV-2 infection in multiple sclerosis patients lacking vaccination responses.
      ,
      • Magnè F
      • Cellerino M
      • Balletto E
      • Aluan K
      • Inglese M
      • Mikulska M
      • Bassetti M.
      Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: An observational study.
      ). Therefore, alternative strategies are needed.

      5.2 Small molecule anti-viral agents

      Have been identified and/or generated to block essential viral function that are distinct from SARS-CoV-2 receptor-binding domain targeting antibodies. These chemicals currently include: remdesivir infusions for hospitalised individuals (
      • Beckerman R
      • Gori A
      • Jeyakumar S
      • Malin JJ
      • Paredes R
      • Póvoa P
      • Smith NJ
      • Teixeira-Pinto A.
      Remdesivir for the treatment of patients hospitalized with COVID-19 receiving supplemental oxygen: a targeted literature review and meta-analysis.
      ) and oral molnupiravir (
      • Jayk Bernal A
      • Gomes da Silva MM
      • Musungaie DB
      • Kovalchuk E
      • Gonzalez A
      • Delos Reyes V
      • Martín-Quirós A
      • Caraco Y
      • Williams-Diaz A
      • Brown ML
      • Du J
      • Pedley A
      • Assaid C
      • Strizki J
      • Grobler JA
      • Shamsuddin HH
      • Tipping R
      • Wan H
      • Paschke A
      • Butterton JR
      • Johnson MG
      • De Anda C
      MOVe-OUT Study Group
      Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients.
      ,
      • Khoo SH
      • FitzGerald R
      • Saunders G
      • Middleton C
      • Ahmed S
      • Edwards CJ
      • Hasdjiyiannaskis D
      • Walker L
      • Rebecca Lyon R
      • Shaw V
      • Mozgunov P
      • Periselneris J
      • Woods C
      • Bullock K
      • Hale C
      • Reynolds H
      • Downs N
      • Ewings S
      • Buadi A
      • Cameron D
      • Edwards T
      • Knox E
      • Donovan-Banfield I
      • Greenhalf W
      • Chiong J
      • Lavelle-Langham L
      • Jacobs M
      • Painter W
      • Holman W
      • Lalloo DG
      • Tetlow M
      • Hiscox JA
      • Jaki T
      • Fletcher T
      • Griffiths G
      AGILE CST-2 Study Group
      A Randomised -Controlled Phase 2 trial of Molnupiravir in unvaccinated and vaccinated individuals with early SARS-CoV-2.
      *), (
      • Wen W
      • Chen C
      • Tang J
      • Wang C
      • Zhou M
      • Cheng Y
      • Zhou X
      • Wu Q
      • Zhang X
      • Feng Z
      • Wang M
      • Mao Q.
      Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19:a meta-analysis.
      ) and ritonavir-enhanced nirmatrelvir (
      • Wen W
      • Chen C
      • Tang J
      • Wang C
      • Zhou M
      • Cheng Y
      • Zhou X
      • Wu Q
      • Zhang X
      • Feng Z
      • Wang M
      • Mao Q.
      Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19:a meta-analysis.
      ,
      • Sun F
      • Lin Y
      • Wang X
      • Gao Y
      • Ye S.
      Paxlovid in patients who are immunocompromised and hospitalised with SARS-CoV-2 infection.
      ) that are used for COVID-19 prophylaxis or for a rapid, post-infection application (
      • Sun F
      • Lin Y
      • Wang X
      • Gao Y
      • Ye S.
      Paxlovid in patients who are immunocompromised and hospitalised with SARS-CoV-2 infection.
      ). Remdesivir prodrug is metabolised by the cytochrome P450 CYP3A4 variant leading to increased bioavailability of other CYP3A4 substrates that include some MS-related drugs (
      • Deb S
      • Reeves AA
      Simulation of remdesivir pharmacokinetics and its drug interactions.
      ,
      • Hirai T
      • Mizuta A
      • Sasaki T
      • Nishikawa K
      • Inoue T
      • Iwamoto T.
      Drug-drug interaction between remdesivir and immunosuppressant agents in a kidney transplant recipient.
      ). Molnupiravir, is another prodrug and is rapidly converted to active drug in plasma, which is excreted with limited hepatic metabolism (
      • Painter WP
      • Holman W
      • Bush JA
      • Almazedi F
      • Malik H
      • Eraut NCJE
      • Morin MJ
      • Szewczyk LJ
      • Painter GR.
      Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2.
      ). This should not unduly influence S1PR modulators. In contrast, ritonavir-enhanced nirmatrelvir may augment the pharmacokinetics of many drugs, including nirmatrelvir, because ritonavir is a potent inhibitor of CYP3A4, CYP2D6 and a number of drug transporters (
      • Heskin J
      • Pallett SJC
      • Mughal N
      • Davies GW
      • Moore LSP
      • Rayment M
      • Jones R.
      Caution required with use of ritonavir-boosted PF-07321332 in COVID-19 management.
      ). Ponesimod is metabolised by a number of cytochrome enzymes including: CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12 without major contribution by any single enzyme and as such is considered unlikely that any major impact on ponesimod metabolism will occur (
      Ponvory Summary of medical product characteristics.
      ). Likewise, fingolimod is metabolised mainly by CYP4F2 and CYP4F3B enzymes and specific CYP3A4 inhibition did not impact fingolimod distribution (
      • Jin Y
      • Zollinger M
      • Borell H
      • Zimmerlin A
      • Patten CJ.
      CYP4F enzymes are responsible for the elimination of fingolimod (FTY720), a novel treatment of relapsing multiple sclerosis.
      ). Ozanimod is extensively metabolised, notably by CYP2C8 and to a small extent by CYP3A4, as such CYP3A4 inhibition had limited impact on ozanimod levels (
      • Tran JQ
      • Zhang P
      • Ghosh A
      • Liu L
      • Syto M
      • Wang X
      • Palmisano M.
      Single-Dose Pharmacokinetics of ozanimod and its major active metabolites alone and in combination with gemfibrozil, itraconazole, or rifampin in healthy subjects: a randomized, parallel-group, open-label study.
      ). However, ozanimod and its active metabolites (notably CC112273) are substrates for p-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), which can be inhibited by ritonavir and could increase ozanimod exposure. However, this would be within safe limits observed in ozanimod trials (
      • Heskin J
      • Pallett SJC
      • Mughal N
      • Davies GW
      • Moore LSP
      • Rayment M
      • Jones R.
      Caution required with use of ritonavir-boosted PF-07321332 in COVID-19 management.
      ). Siponimod carries a warning that it should be avoided with CYP2C9 and CYP3A4 inhibitors (
      • Huth F
      • Gardin A
      • Umehara K
      • He H.
      Prediction of the impact of cytochrome P450 2C9 genotypes on the drug-drug interaction potential of siponimod with physiologically-based pharmacokinetic modeling: A comprehensive approach for drug label recommendations.