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Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United KingdomCentre for Oral Immunobiology and Regenerative Medicine, Dental Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United KingdomClinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United KingdomClinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
Treatment with fingolimod is not associated with a worse prognosis from COVID-19.
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Fingolimod inhibits antibody and measureable T cell responses due to SARS-COV-2 vaccination.
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Fingolimod seems to reduce seroconversion compared to other S1PR modulators.
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Vaccine antibody responses are probably controlled by S1PR1, S1PR2 and S1PR4.
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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.
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 (
). 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 (
). Active inflammation, seen by new lesion activity on imaging and/or clinical relapse, can be targeted by a large number of disease modifying treatments (
). 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 (
). 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 (
Current migration inhibitors affect both T and B cells, which are central, interacting parts of the immune system that deals with infection and vaccination (
). 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 (
). 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 (
), 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 (
), 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 (
). The biology of the disease modifying MS treatments indicates that they have limited to no impact on coagulation and microthrombi formation and vice versa (
). 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 (
). 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 (
). 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 (
) 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 (
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.
). 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 (
In contrast fingolimod (Fig. 1), which is a lymphocyte migration inhibitor, was not associated with a worse outcome following natural SARS-CoV-2 infection (
). 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 (
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.
Pharmacodynamic effects of steady-state fingolimod on antibody response in healthy volunteers: a 4-week, randomized, placebo-controlled, parallel-group, multiple-dose study.
). 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 (
). 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 (
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 (
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.
). 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 (
CovaXiMS study group Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.
). This indicates that the clinical responses observed can be attributed to the chemistry and biology of the different agents. It therefore remained to be seen whether there could be any differences between fingolimod and the other sphingosine-one-phosphate receptor (S1PR) modulators, approved shortly before or during the COVID-19 pandemic (Fig. 1) (
), which may predict or explain likely COVID-19 infection and vaccine responses that may affect the risk-benefit balance.
Fig. 1Sphinogsine-1-phosphate receptor modulators used in multiple sclerosis. Chemical structures, relative elimination half-lives, the presence of active metabolites (M) and receptor binding and distribution profiles were obtaining from the Summary of Medical Product Characteristic reported at the European Medicines Agency website and the literature. Ponesimod has low affinity for S1PR5. Created with Biorender.com.
Immune cell profiling during switching from natalizumab to fingolimod reveals differential effects on systemic immune-regulatory networks and on trafficking of non-t cell populations into the cerebrospinal fluid-results from the ToFingo Successor Study.
). Sphingosine-1-phosphate acts via a number of G-protein-coupled S1P receptors (Fig. 1, Table 2). Fingolimod is likewise phosphorylated by sphingosine kinase enzymes to create an active molecule that performs important signalling function related notably to the vascular and immune systems (
). 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 (
). The current S1PR modulators have distinct S1PR binding affinities, pharmacokinetics and different use-indications (Fig. 1).
In the United States of America: fingolimod, siponimod, ozanimod and ponesimod all have a similar utility and are licensed for clinically-isolated syndrome, relapsing MS and active secondary progressive MS (
). 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 (
). 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 (
). 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 (
). 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.
Treatment
S1PR targeted
Time to Cmax
Approximate Elimination half-live
Median time lymphocyte recovery
Ponesimod
1
2–4h
33 h
1 week
Siponimod
1,5
4h
30 h
10 days
Ozanimod
1,5
6–8h
21 h/11days(CC112273)
30 days
Fingolimod
1,3,4,5
12–26h
6–9days
1–2 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
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 (
). 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) (
Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator.
) 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 (
Maximal effect at 10,000 nM on S1PR4/S1PR5 was 18/42%, respectively of the effect on S1P response, so was not only less efficacious but also less potent than S1P. The standard daily doses are: 0.5 mg fingolimod, 1 mg siponimod, 0.92 mg ozanimod or 20 mg ponesimod.
Maximal effect at 10,000 nM on S1PR4/S1PR5 was 18/42%, respectively of the effect on S1P response, so was not only less efficacious but also less potent than S1P. The standard daily doses are: 0.5 mg fingolimod, 1 mg siponimod, 0.92 mg ozanimod or 20 mg ponesimod.
The S1P1R binding affinities of sphinogsine-1-phosphate (S1P) and the S1PR modulators were extracted from the literature. The results report the aIC50 or b,cEC50 binding levels using either.
a competitive radio-ligand binding.
b gamma GTPS or.
c beta-arrestin binding assays.
d Maximal effect at 10,000 nM on S1PR4/S1PR5 was 18/42%, respectively of the effect on S1P response, so was not only less efficacious but also less potent than S1P. The standard daily doses are: 0.5 mg fingolimod, 1 mg siponimod, 0.92 mg ozanimod or 20 mg ponesimod.
). Ponesimod targets largely S1PR1, with lower affinities and partial activity for other receptors, notably S1PR5, and inhibits relapsing MS (Fig. 1, Table 2) (
). They also target S1PR5 on oligodendrocytes and their precursors to potentially better influence remyelination (Fig. 1, Table 2) and do not require the action of phosphorylating S1P kinases for activity (
). 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 (
), 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 (
). 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 (
). 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 (
). 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 (
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 (
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 (
). 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 (
). 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 (
). The effector memory (CD45RO+, CCR7+) and notably effector T-cells (CD45RA+, CCR7-), which will give the protective anti-viral responses in tissues can enter the circulation to promote defence against pathogens (
). 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 (
). 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 (
Expression of CCR7 and CD45RA in CD4+ and CD8+ subsets in cerebrospinal fluid of 134 patients with inflammatory and non-inflammatory neurological diseases.
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 (
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.
). 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 (
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.
). 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 (
CovaXiMS study group Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.
). Antibody responses can be generated within the lymphoid tissue from immature and naïve B cells, which seem to express many S1PR (Fig. 2) and thus may not require re-circulation to tissues to induce antibody-producing plasma cells that could facilitate removal of the SARS-CoV-2 virus (
). 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 (
Fig. 2Sphinogsine-1-phosphate receptor distribution in human and mouse cells. The S1PR mRNA expression distributions from cells and tissues were extracted from Affimetrix RNAseq data in the human Primary Cell Atlas or the mouse GeneAtlas MOE430 gcrma datasets at www.biogps.org, using the indicated S1PR-specific probes. The results represent the mean ± standard error of the mean expression of 2–21 individual samples of normalised expression data. Human macrophages and dendritic cells were monocyte-derived and the monocytes expressing S1PR3 were from the CD14+ subset (935±55a.u.) compared to the CD16+ (76±55a.u. n = 3). a.u. arbitrary units. The human natural killer cells subset examined, expressed CD56, CD62 antigens.
Vaccine responses during fingolimod treatment are blunted compared to untreated individuals with a seroconversion rate of 60.2% in a meta-analysis of n = 785 people treated with S1PR modulators, largely taking fingolimod n = 764 (
). 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) (
). 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) (
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.
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.
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.
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.
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.
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.
COVID-19 antibody response by vaccine type and lymphocyte count in RMS patients on ponesimod: results from Phase 2 long-term extension study AC-058B202.
Indicates that the public domain information may not have been peer-reviewed.
11/11 (100%) Exposed
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“
“
33/38 (86.8%) Naïve
“
“
“
29/32 (90.6%) mRNA
“
“
“
Information was extracted from data tables from a meta-analysis of 31 studies on the influence fingolimod treatment on SARS-CoV-2 vaccination (two doses). This was contrasted with individual public domain studies of SARS-CoV-2 vaccination in people treated with either siponimod, ozanimod or ponesimod. The results show the number of serological responders, defined within their studies, from the total analysed in response to any Index SARS-CoV-2 vaccine (varied) or stratified into those receiving only mRNA vaccines. Data was also stratified into those potentially previously exposed to COVID-19 infection, indicated by serological responses to SARS-CoV-2 nucleocapsid, or were considered to be infection-naïve in the absence of nucleocapsid serology. Where defined the SARS-Cov-2, antibody detection assay and manufacturer was indicated and these included electro-chemiluminescent immunoassay (ECLIA) and enzyme-linked immunosorbent assays (ELISA). It is indicated whether SARS-CoV-2 T-cell recall responses were performed. The source references are indicated.
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 (
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.
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.
COVID-19 antibody response by vaccine type and lymphocyte count in RMS patients on ponesimod: results from Phase 2 long-term extension study AC-058B202.
). This could suggest that S1PR3 and S1PR4, which are widely expressed by the immune system (Fig. 2), contribute to lower antibody titres following vaccination, as suggested by the underlying biology.
). 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 (
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) (
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 (
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.
). 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 (
). 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) (
). 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 (
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.
). 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 (
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.
CovaXiMS study group on behalf of the Italian Covid-19 Alliance in MS. Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
). Likewise, in another similar fingolimod study, again a median antibody titre of only 26.7 U/ml (n = 71) was reported in infection-naïve, tozinameran-vaccinated individuals (
). Importantly, it was reported that only 14/71 (19.1%) fingolimod-treated, infection-naïve individuals developed an index SARS-CoV-2 strain neutralizing titre of >133 U/ml occurred in fingolimod-treated individuals (
). 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 (
) 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) (
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.
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 (
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Indicates that the public domain information may not have been peer-reviewed.