Sage Journals: Discover world-class research

Abstract

People with multiple sclerosis (pwMS) have an increased risk of infection. As disease-modifying therapies (DMTs) and other treatments may interact with the immune system, there may be concerns about vaccine efficacy and safety. Therefore, it is important to evaluate possible interactions between DMTs and vaccines. The fumarates, dimethyl fumarate, diroximel fumarate, and monomethyl fumarate, are approved for the treatment of relapsing multiple sclerosis. This review assesses the evidence on vaccine response in pwMS treated with fumarates, with a particular focus on COVID-19 vaccines. Treatment with fumarates does not appear to result in blunting of humoral responses to vaccination; for COVID-19 vaccines, particularly RNA-based vaccines, evidence indicates antibody responses similar to those of healthy recipients. While data on the effect of fumarates on T-cell responses are limited, they do not indicate any significant blunting. COVID-19 vaccines impart a similar degree of protection against severe COVID-19 infection for pwMS on fumarates as in the general population. Adverse reactions following vaccination are generally consistent with those observed in the wider population; no additional safety signals have emerged in those on fumarates. Additionally, no increase in relapse has been observed in pwMS following vaccination. In pwMS receiving fumarates, vaccination is generally safe and elicits protective immune responses.

Keywords

Multiple sclerosis COVID-19 vaccines fumarates dimethyl fumarate diroximel fumarate

Introduction

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system and is the most common non-traumatic disabling neurological disease in young adults, affecting approximately 2.5 million people worldwide.¹ Currently, there are several different classes of disease-modifying therapies (DMTs) available for the treatment of MS, which selectively modulate or suppress the immune system.²

People with MS (pwMS) are at increased risk of infection compared with the general population,³ potentially as a result of immunosuppression due to treatment or as a consequence of MS-related functional limitations and disability.^4–6 The risk of serious infection is most highly increased in pwMS with more severe disability and in those with progressive MS.⁶ Therefore, the risk of infection in this patient population highlights the importance of mitigation strategies to prevent infections, including vaccination, and risk–benefit assessment in the selection of suitable DMTs.^4,7,8 However, there may be some degree of hesitancy to get vaccinated due to fears of relapse and other safety concerns, along with insufficient or inaccurate knowledge about vaccines.^9,10

Vaccination in patients with MS

Increasing protection against infectious diseases in pwMS has received much attention since the global COVID-19 pandemic was declared in 2020, not least because the use of certain DMTs has been associated with a higher risk of infection and increased severity of COVID-19.¹¹ Numerous studies have indicated an increased risk for severe COVID-19 in people treated with anti-CD20 monoclonal antibodies (mAbs) compared with other DMTs.^11–13 Pivotal trials for both the Moderna mRNA-1273 and Pfizer/BioNTech BNT162b2 demonstrated >90% efficacy at preventing symptomatic COVID-19, and nearly eliminated severe disease.^14,15 In a study of 317 pwMS, full vaccination against COVID-19 (n = 97) was associated with a significantly decreased risk of severe COVID-19 infection at a median of 5 months post-first vaccination compared with unvaccinated patients.¹⁶

With this review, we sought to examine the available evidence regarding the vaccine response in pwMS receiving treatment with oral fumarates, with a particular focus on influenza and COVID-19 vaccines, and with consideration given to dosing and timing of DMT. Briefly, literature searches were conducted using PubMed from March 2022 and carried out periodically until June 2023 to identify any key developments. Searches were conducted using combinations of the following terms: “COVID-19”; “vaccine”; “vaccination”; “multiple sclerosis”; “MS”; “disease-modifying therapy”; “DMT”. Searches specifically related to fumarates included the term “fumarate.” Additional references were sourced based on the author group's own knowledge of the area. Recommendations from MS groups and societies were accessed manually.

Vaccine response with DMTs

While it is evident that COVID-19 vaccines are effective at reducing the risk of severe infection, prior or concomitant treatment with DMT may impact vaccine efficacy. Some DMTs, particularly anti-CD20s and sphingosine-1-phosphate receptor modulators (S1PRMs), appear to blunt humoral responses both to vaccines in general,^17,18 and specifically to COVID-19 vaccines.^19–21 Furthermore, T-cell responses are preserved with anti-CD20s, glatiramer acetate, natalizumab, fumarates, and other DMTs, but may not be preserved with S1PRMs.^20–22 Accordingly, studies have revealed differences in the clinical efficacy of COVID-19 vaccines dependent on the type of DMT a patient receives. Post-vaccination, pwMS on anti-CD20 therapy or fingolimod demonstrate significantly higher risks of breakthrough COVID-19 infections compared with pwMS on other DMTs and compared with the general population.^23–25 COVID-19 vaccine efficacy was preserved in pwMS receiving other DMTs, including dimethyl fumarate (DMF), glatiramer acetate, interferons (IFNs), natalizumab, and teriflunomide.^23,25 Interactions between DMTs and the immune response present a significant concern for the timing of vaccination and the preservation of vaccine efficacy in pwMS. Vaccination is an important component of patient care and is recommended by several MS groups and societies worldwide, with considerations for timing based on the vaccine type, infection risk, and specific DMT class (Table 1).^26–32

Table 1.

Guidelines for vaccination in pwMS.

Society/Group	Country/region	General recommendations	Specific vaccine recommendations
National MS Society²⁶ and American Academy of Neurology²⁷	USA	Vaccinate according to standard schedule, unless there are contraindications Delay vaccination if experiencing a relapse Discuss MS medication	Live and live attenuated vaccines are not recommended for those on certain immune-suppressing DMTs Annual influenza vaccine is recommended Most people with relapsing and progressive forms of MS should be vaccinated against COVID-19
ECTRIMS-EAN²⁸	Europe	Vaccines are not associated with increased risk of relapses or disability accrual (with/without DMTs) and the benefit of vaccination greatly outweighs any potential risks	Vaccines with extended use in high-risk populations (immunosuppression), such as influenza or pneumococcal vaccines, should also be considered Additional vaccines with more restricted indications such as hepatitis B, human papillomavirus, and/or herpes zoster can also be recommended in specific situations
French MS Society³²	France	Vaccinate according to the French vaccination schedule	Seasonal influenza vaccination is recommended Live attenuated vaccines are contraindicated in those recently treated with immunosuppressive agents; other vaccines can be proposed whatever the treatment, but their effectiveness may be partly reduced with some agents
NICE²⁹	UK	Vaccinate according to the UK vaccination schedule (JCVI)
MS Therapy Consensus Group³¹	Germany, Austria, Switzerland	In principle, MS patients must be vaccinated following national guidelines For those on DMT, vaccination should still be given as there is a reasonable prospect of achieving a sufficient vaccine response	MS patients should be vaccinated against COVID-19 Live vaccines are generally contraindicated in pwMS receiving immunosuppressive treatment or require careful benefit/risk assessment. The interval between live vaccination and initiation of immunosuppressive therapy should be ≥6 weeks
MS International Federation³⁰	Global network of MS organizations		Seasonal influenza vaccination is recommended COVID-19 vaccination is recommended (no delay or adjustment to DMT needed for those on fumarates)

DMT: disease-modifying therapy; JCVI: Joint Committee on Vaccination and Immunisation; MS: multiple sclerosis; pwMS: people with MS.

DMF and diroximel fumarate (DRF) are oral DMTs that have been approved in Europe and the USA, as well as in other countries, for the treatment of relapsing forms of MS,³³ and share the same active metabolite, monomethyl fumarate (MMF). MMF is itself approved in the USA as an oral DMT for the treatment of relapsing forms of MS. The approved therapeutic doses of DMF (240 mg) and DRF (462 mg) produce bioequivalent exposure of MMF; therefore, comparable efficacy and safety profiles are expected at these doses.³⁴ It is anticipated that individual oral fumarate DMTs would have similar effects on vaccine response, although the data for DRF and MMF are currently limited.

Effects of fumarates on immune response and vaccine response

Mechanisms of action and immunological effects of fumarates in patients with MS

Fumarates demonstrate anti-inflammatory and antioxidant activity and appear to exert their therapeutic effects in pwMS through multiple mechanisms. In the central nervous system, fumarates may have a neuroprotective effect through the induction of antioxidant proteins via the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent pathway.³⁵ In the peripheral immune system, treatment with fumarates is associated with a decline in absolute lymphocyte counts and subsequent stabilization after 24 weeks.^36–39 Depletion of T and B cells, and a subsequent reduction in pro-inflammatory cytokines, may be the immunological process by which DMF and DRF impart their effect on MS disease activity.^39–41 However, specific subsets of T, B, and natural killer (NK) cells are affected to varying degrees.^38,39 With DMF treatment, the most significant declines from baseline occur in memory subsets of T-cell and B-cell populations.^39,41 In contrast, subsets of naive T and B cells increase, and the proportions of regulatory T cells are maintained.^39,41 These changes may be mediated via immunoregulatory CD56^bright NK cells, since the increase in the proportion of CD56^bright NK cells with DMF treatment is correlated with reductions in CD8⁺ T cells, CD4⁺ and CD8⁺ memory T cells, and cytokine-producing CD4⁺ and CD8⁺ T cells.^38,40 Overall, this represents a general shift away from pro-inflammatory lymphocytes and toward an anti-inflammatory profile, with increases in naive cells potentially being beneficial for generating an effective response to vaccination (Figure 1). The declines in CD4⁺ and CD8⁺ T cells and memory B cells and the shift to an anti-inflammatory response may be associated with the improvements observed in MS disease activity with DMF treatment.^39,41 The end result more closely resembles immune homeostasis rather than an overt blunting of the immune response, as might occur with the depletion of immune cell populations. Accordingly, innate immune cell activation and antigen presentation are not expected to be impacted by fumarates, and the capacity to mount effective T-cell responses to antigens would be preserved.²⁰

Figure 1.

Fumarates and the immune response to vaccination. Treatment with fumarates is associated with a shift away from a pro-inflammatory profile and an increase in naive/anti-inflammatory lymphocytes.

Response to vaccines in patients with MS receiving fumarates

Numerous studies have assessed the effect of fumarates on immune response in pwMS; current evidence regarding the impact of DMF and DRF on various vaccine types is summarized in Table 2. In a prospective study including 20 pwMS treated with DMF, the efficacy of the seasonal inactivated influenza vaccines 2020/2021 was assessed in pwMS based on the proportions who reached cut-off for seroprotection (hemagglutination inhibition assay of ≥1:40) or had an antibody increase of 4-fold for at least two of the four influenza strains. All pwMS were responders 30 days after immunization with the influenza vaccine, indicating an adequate humoral response.⁴² As a marker for neuroaxonal damage, serum neurofilament light chain (sNfL) levels were assessed as the primary safety outcome and indicated no change from baseline to 30 days after vaccination in pwMS on DMF, possibly signifying that no reactivation of MS occurred. In addition, no significant differences were observed in sNfL level between people on DMF and healthy controls.⁴² Following COVID-19 infection in two healthy controls and one pwMS, sNfL levels increased by more than 10 pg/ml in both control participants, but remained stable in the patient on DMF.⁴²

Table 2.

Evidence on the effect of treatment with DMF or DRF on response to selected vaccines.

Study	Vaccine	Study design/methods	Results	Conclusion
Inactivated virus vaccines
Moser et al.⁴²	Seasonal influenza vaccine	Prospective study of 20 pwMS treated with DMF (15 healthy controls)	All patients treated with DMF responded to immunization versus 53% of controls Higher proportions of healthy controls already had influenza-antibody titers ≥1:40 at baseline (53% vs. 41%, p = 0.174) sNfL levels were comparable among both groups at baseline and did not increase 34 days after vaccination No clinical or radiological disease reactivation was found	All DMF-treated patients mounted an adequate humoral immune response to the influenza vaccine Influenza immunization not associated with clinical or subclinical disease reactivation
Protein subunit and toxoid vaccines
von Hehn et al.⁴³	Tetanus–diphtheria toxoid; pneumococcal 23-polyvalent vaccine; meningococcal (groups A, C, W-135, and Y) oligosaccharide CRM197 conjugate	A single open-label, multicenter study Examined effects of DMF (n = 38) versus non-pegylated IFN (n = 33) on immune response to three vaccinations	Responder rates (≥2-fold rise in IgG titers) were comparable between DMF- and IFN-treated groups (all p > 0.05) for: Tetanus–diphtheria vaccination (68% vs. 73%) Diphtheria antitoxoid vaccination (58% vs. 61%) Pneumococcal serotype 3 vaccination (66% vs. 79%) Pneumococcal serotype 8 vaccination (95% vs. 88%) Meningococcal serogroup C vaccination (53% vs. 53%) No meaningful differences were observed between groups in the proportion of responders stratified by age category or lymphocyte count	DMF does not inhibit humoral immune function in pwMS
Nucleic acid and recombinant vector vaccines
Jaber et al.⁴⁴	Moderna mRNA-1273 COVID-19 vaccine	Ongoing, prospective, open-label observational study 45 pwMS treated with natalizumab (n = 12), ocrelizumab (n = 14), DMF or DRF (n = 11), and IFN (n = 6) Primary endpoint: anti-COVID-19 spike RBD geometric mean titers at 8 weeks from initial vaccine dose	All natalizumab, fumarate, and IFN-treated patients generated similar humoral immune responses to the COVID-19 mRNA vaccine Ocrelizumab-treated pwMS demonstrated dramatically reduced anti-COVID-19 antibody titers; most participants had no detectable antibody Ocrelizumab participants had more myalgia with mRNA-1273 and a trend toward higher rates of most side effects	In pwMS treated with DMF or DRF, or other DMTs, humoral response to mRNA-1273 COVID-19 vaccine was preserved in patients treated with fumarates and was similar to those receiving IFNs or natalizumab
Cohen et al.⁴⁵	COVID-19 vaccine: AstraZeneca, Pfizer/BioNTech, Moderna, Johnson & Johnson	Real-world study of 322 pwMS; 91.9% received an mRNA vaccine Post–COVID-19 vaccination blood samples across multiple DMTs were tested for COVID-19 IgG response	Post-vaccination reactive IgG rates: 40% for anti-CD20 (32/80 patients) 41% for S1PRMs (16/39) 100% for all other classes, including the no-DMT group	Anti-CD20s and S1PRMs reduce IgG response to COVID-19 vaccination IgG response to COVID-19 vaccination was preserved in pwMS treated with other DMTs, including alemtuzumab, fumarates, GA, IFNs, natalizumab, and teriflunomide, and in those with no DMT
Pitzalis et al.⁴⁶	Pfizer/BioNTech COVID-19 mRNA vaccine (BNT162b2)	Sardinian study in 912 pwMS and 63 healthy controls tested for COVID-19 response using anti-spike protein–based serology	High levels of anti-spike antibodies post-COVID-19 vaccination in pwMS treated with DMF, IFN, alemtuzumab, or GA; no significant difference vs untreated pwMS pwMS treated with natalizumab, teriflunomide, azathioprine, fingolimod, ocrelizumab, and rituximab showed significantly lower humoral responses compared with untreated patients Older age, male sex, and active smoking were significantly associated with lower COVID-19 antibody titers	Humoral response to BNT162b2 is preserved in pwMS treated with DMF
Sabatino et al.²⁰	COVID-19 vaccine (BNT162b2 or mRNA-1273)	A prospective, observational study of 80 participants (pwMS and healthy controls) to assess COVID-19 vaccine-induced humoral and cellular immune responses pwMS either received no treatment or were treated with GA, DMF, natalizumab, S1PRMs, or anti-CD20s	Following vaccination, anti-spike IgG levels were similar between healthy controls and patients with untreated MS and those receiving GA, DMF, or natalizumab, but were reduced in anti-CD20 and S1PRM-treated patients Patients treated with S1PRMs or anti-CD20s had significantly reduced levels of total spike and spike RBD IgG Spike-specific CD4⁺ and CD8⁺ T-cell reactivity remained robust across all groups, except in S1PRM-treated patients, in whom postvaccine CD4⁺ T-cell responses were attenuated	MS therapies differentially affected COVID-19 vaccine-induced antibody and T-cell immunity and function pwMS treated with DMF mounted similar humoral and cell-mediated responses to COVID-19 vaccination as untreated pwMS
Achiron et al.²¹	Pfizer/BioNTech COVID-19 mRNA vaccine (BNT162b2)	Prospective, cross-sectional study assessing COVID-19 IgG response up to 6 months post-vaccination with BNT162b2 in 414 pwMS and 89 healthy subjects	Protective response was demonstrated in untreated pwMS (n = 76, 100%), and those treated with cladribine (n = 48, 100%), DMF (n = 35, 100%), natalizumab (n = 32, 100%), teriflunomide (n = 39, 100%), and alemtuzumab (n = 22, 86.4%), similar to healthy subjects (n = 89, 97.8%) Response was decreased in pwMS who received fingolimod (n = 42, 9.5%) or ocrelizumab (n = 114, 22.8%)	No significant statistical difference was found in post-vaccination COVID-19 IgG between healthy subjects and pwMS treated with DMF For patients treated with ocrelizumab or fingolimod, these treatments might prevent the development of a favorable immune response
Wu et al.⁴⁷	Various COVID-19 vaccines	Meta-analysis of 48 studies comprising 6860 pwMS Estimated the risk of impaired response to vaccination in pwMS receiving DMTs	Assessing 14 studies on the efficacy of the COVID-19 vaccine in patients on DMF indicated a comparable serological response with the untreated group and no significant difference in the post-vaccination seroconversion rate pwMS treated with anti-CD20 s or S1PRMs had attenuated serologic response after vaccination compared with those without DMTs pwMS vaccinated within 6 months since the last anti-CD20 therapy were at significantly higher risk of a reduced response compared with those receiving anti-CD20 therapy ≥6 months before vaccination (p = 0.001) No significant difference was found between pwMS on anti-CD20 and those without DMTs after vaccination; S1PRM treatment was marginally associated with impaired cellular response (p = 0.03)	Antibody responses in pwMS on DMF post-COVID-19 vaccination were comparable to those of pwMS not receiving DMT

DMF: dimethyl fumarate; DMT: disease-modifying therapy; DRF: diroximel fumarate; GA: glatiramer acetate; IFN: interferon; IgG: immunoglobulin G; MS: multiple sclerosis; pwMS: people with MS; RBD: receptor binding domain; S1PRM: sphingosine-1-phosphate receptor modulator; sNfL: serum neurofilament light chain.

An open-label study of patients receiving DMF or IFN for treatment of MS evaluated the immune response to three vaccines: tetanus–diphtheria toxoid to assess T-cell-dependent humoral response; pneumococcal 23-polyvalent vaccine to assess T-cell-independent humoral response; and meningococcal oligosaccharide CRM₁₉₇ conjugate to assess T-cell-dependent neoantigen response.⁴³ Between DMF and IFN groups, responder rates (≥2-fold rise in anti-tetanus serum immunoglobulin G [IgG] levels) were comparable for all tested vaccines and no meaningful differences were observed between groups when stratified by age category or lymphocyte count.⁴³ These outcomes support that patients treated with DMF can mount humoral responses following vaccination comparable to those of patients on IFN.⁴³

Response to COVID-19 vaccines in patients with MS receiving fumarates

Most of the published data regarding efficacy in pwMS of vaccines developed against COVID-19 were generated in those who received mRNA vaccines, specifically Pfizer/BioNTech BNT162b2 and Moderna mRNA-1273. Since their authorizations for use, various studies have assessed the effect of DMTs, including DMF, on the immune response to these vaccines.

In a study of pwMS in Sardinia, Italy, it was observed that IgG titers elicited following two doses of Pfizer/BioNTech BNT162b2 in patients receiving DMF (n = 151) were similar to those of healthy controls (n = 63).⁴⁶ A real-world study of 322 pwMS from the USA, Germany, and Spain, who were vaccinated against COVID-19, also showed IgG response to be preserved in all patients who were treated with fumarates (DMF, n = 32; DRF, n = 5).⁴⁵ Most of these patients (92%) had received an mRNA vaccine, either Pfizer/BioNTech BNT162b2 or Moderna mRNA-1273.⁴⁵ Similarly, in a prospective, open-label, observational study of pwMS at a single center in the USA treated with fumarates, natalizumab, ocrelizumab, or IFN, all patients who received fumarates (n = 11; DMF or DRF) generated detectable anti-COVID-19 spike receptor binding domain (RBD) IgG titers 8 weeks after the initial dose of the Moderna mRNA-1273 COVID-19 vaccine, and mean IgG titers were similar to those in patients receiving natalizumab or IFN.⁴⁴ In an observational cohort study of pwMS receiving DMT (n = 338) at a center in Israel, all those on DMF (n = 35) demonstrated detectable anti-COVID-19 IgG after receiving the Pfizer/BioNTech BNT162b2 mRNA vaccine, with similar levels of IgG antibodies to healthy vaccinated subjects and in patients with untreated MS.²¹ An Austrian study of pwMS on DMT who received COVID-19 vaccines reported seroconversion in 62 of the 63 patients who were on DMF, a rate of 98.4%.¹⁹

The Oxford/AstraZeneca ChAdOx1-S and Johnson & Johnson/Janssen Ad26.COV2.S COVID-19 vaccines are adenoviral vector vaccines. Data for pwMS treated with DMF who received these vaccines are more limited compared with mRNA vaccines—for example, in the real-world study reported above⁴⁵ only three out of 37 patients receiving fumarates received a recombinant viral vector vaccine (ChAdOx1-S, n = 1; Ad26.COV2.S, n = 2)—however, some outcomes have been reported. In a study of pwMS at centers in the UK, for patients who were on DMF, seroconversion rates were greater in those who received the Pfizer/BioNTech BNT162b2 vaccine (100%; n = 14/14) compared with those who received the Oxford/AstraZeneca ChAdOx1-S vaccine (80%; n = 12/15).⁴⁸ However, the corresponding rates in people with untreated MS (BNT162b2: 100% [n = 41 out of 41]; ChAdOx1-S: 93% [n = 27 out of 29]) suggest the suboptimal seroconversion rate observed was more likely a consequence of adenoviral vector vaccine type, rather than due to treatment with DMF.⁴⁸

Due to the complex nature of cellular immunity, T-cell responses are more challenging to characterize and quantify than antibody responses,⁴⁹ resulting in fewer studies and smaller sample sizes in the published literature on COVID-19 vaccine response. A prospective, observational study of 80 pwMS in the USA indicated that those treated with DMF mounted humoral and cell-mediated responses to COVID-19 vaccination (BNT162b2, mRNA-1273, or Ad26.COV2.S) similar to those of untreated MS patients.²⁰ Post-vaccination, spike-specific CD8⁺ T cells were significantly increased in the DMF patient cohort. However, these outcomes were based on a small group of patients with DMF (n = 5), and therefore, further data on the T-cell response following vaccination in pwMS receiving DMF would be valuable.²⁰

Few studies have assessed the responses in pwMS on DMF following booster doses of COVID-19 vaccines, but outcomes reported so far for humoral responses indicate IgG titers and seroconversion rates comparable to those in healthy controls.^50,51 In an observational study, all 15 pwMS on DMF who received booster doses of BNT162b2 or Sinovac vaccines were seropositive at least 2 weeks afterward.⁵⁰ Median IgG titers in 11 pwMS treated with DMF were comparable to those observed in healthy controls, 21 days after a third dose of BNT162b2.⁵¹ However, a study assessing IFN-γ response to severe acute respiratory syndrome-coronavirus-2 spike protein antigens as a marker for the cellular response found that responses were not significantly different in pwMS on DMF following a booster vaccine, and responder rates were similar after two or three doses (68.4% and 71.4%, respectively).⁵²

Meta-analyses of COVID-19 vaccine response in pwMS found no significant effect of DMF on the serological response or seroconversion rates post-vaccination compared with untreated patients.^47,53 Based on the reported data, there is considerable evidence that the humoral response to COVID-19 mRNA vaccines is preserved in pwMS treated with fumarates; however, data are predominantly for patients receiving DMF rather than DRF. Further understanding of specific aspects would also be of significant benefit, including the effects of fumarates on the overall response to recombinant vector vaccines and on the cellular response to COVID-19 vaccines, as well as their impact on the overall clinical protection conferred by vaccines, including the risks of severe disease.

Safety of vaccination in patients with MS treated with fumarates

Most vaccine types do not present safety concerns for pwMS receiving treatment with DMTs. However, the reactivation of MS following vaccination remains a concern among pwMS. A 2021 review found little evidence to support vaccination triggering autoimmune responses in pwMS, with the exception of yellow fever (live attenuated) vaccine.⁵⁴ However, two retrospective cohort studies, including 128 pwMS (all relapsing-remitting MS) and 23 pwMS (20 with relapsing-remitting MS and three with primary progressive MS), respectively, indicated that yellow fever vaccine was not associated with worsening MS.^55,56 Across 178 pwMS who had predominantly received either the inactivated COVID-19 Sinovac-Coronavac vaccine or the Pfizer/BioNTech BNT162b2 mRNA vaccine, no significant change in relapse rate was observed in the 8 weeks post-vaccination compared with the 8 weeks prior to vaccination.⁵⁷ A further study of pwMS who received the BNT162b2 vaccine found no increase in disease activity and rates of relapse consistent with those in non-vaccinated patients.⁵⁸

As described earlier, sNfL levels, when assessed as a marker for disease activity in 20 pwMS on DMF who received the seasonal influenza vaccine, did not change significantly in the 4 weeks post-vaccination compared with baseline, and showed no significant difference from levels observed in healthy controls.⁴² In addition, in the 4 weeks following vaccination, there were no relapses, neurological deteriorations, or gadolinium-enhancing lesions, while 80% (n = 16 out of 20) of patients showed no new/newly enlarging lesions compared with the most recent magnetic resonance imaging prior to vaccination.⁴² Together, these outcomes indicate that in pwMS treated with DMF, there was no exacerbation of clinical or subclinical disease activity post-vaccination.⁴²

In addition to concerns about vaccine-induced relapses, general tolerability may also be of concern for those who are considering vaccination. In pwMS who received tetanus–diphtheria toxoid, pneumococcal 23-polyvalent vaccine, and meningococcal oligosaccharide CRM197 conjugate vaccines, vaccination-emergent adverse events occurred in 42% of patients on DMF and 55% of patients on IFN; most were mild or moderate.⁴³ Adverse event profiles of the recently approved COVID-19 vaccinations in pwMS appear to be generally consistent with safety profiles observed in the general population.^10,57 In an observational study of 719 pwMS who received a COVID-19 vaccine (BNT162b2, mRNA-1273, ChAdOx1-S vaccine, or Ad26.COV2.S), 64% and 74% of the study population experienced reactions 24 h after the first and second shots, respectively, including pain at the injection site, fatigue, and headache.¹⁰ The same three adverse events were found to be among the most common in 11 pwMS on DMF or DRF who received the mRNA-1273 vaccine in a prospective observational study of 45 pwMS, consistent with the events observed in those receiving natalizumab, ocrelizumab, or IFN beta.⁴⁴ Multivariate regression suggested that people receiving fumarates may have a lower risk of reactions after a second vaccine shot compared with those not on DMT.¹⁰

Summary

There is substantial evidence accumulating that pwMS treated with fumarates will mount adequate humoral responses to vaccinations, similar to healthy controls and pwMS treated with IFNs.^42,43 Furthermore, smaller studies have shown that spike-specific CD4⁺ and CD8⁺ T-cell responses remain intact in pwMS treated with DMF.²⁰ In pwMS receiving fumarates, reactivation of disease activity has not been observed following vaccination.⁴² Most vaccines have been shown to be safe in MS, perhaps with the exception of the yellow fever vaccine, which might contribute to disease activity.⁵⁴ Since vaccine hesitancy is common among pwMS, this presents an opportunity for improving patient education.⁹

However, some data gaps remain to be addressed. Compared with the Pfizer/BioNTech BNT162b2 and Moderna mRNA-1273 vaccines, data relating to the effects of fumarates on vaccine response are less complete for other vaccines. Specifically, there are limited data available relating to immunization with live attenuated vaccines in patients receiving fumarates. Further study of the T-cell response following vaccination in people receiving fumarates for MS is required to elucidate how vaccine efficacy could be affected by these agents, especially for those with on-treatment lymphopenia. Finally, data on the overall effectiveness of COVID-19 vaccines in preventing severe disease and hospitalizations in pwMS on fumarates would be of value to prescribers and patients.

Clinicians should use their medical judgment and assess recommendations for vaccination on an individual basis for pwMS. The decision of whether or not to vaccinate should be determined based on the risks of infection and the risks of vaccination, as well as any relevant lifestyle factors that may influence a patient's exposure to a pathogen.⁵⁴ For non-live vaccines such as those against COVID-19, which significantly reduce the likelihood of severe infection and hospitalization, based on the currently available evidence in pwMS we recommend that no interruption or delay in treatment with fumarates is needed.

Footnotes

Acknowledgements

Medical writing support, based on input from authors, was provided by David Pertab, PhD, Excel Scientific Solutions (Glasgow, UK), and funded by Biogen.

Author contributions

The authors had full editorial control of the paper and provided their final approval of all content.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MAT received research funding support from Biogen; consulting fees for medical advisory boards from Alexion, Biogen, Genentech, and TG Therapeutics; and speaker fees from Genentech. SV received lecturing fees, travel grants, and research support from Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche, Sandoz, Sanofi-Genzyme, and Teva. MS and AG employees of and held stock/stock options in Biogen at the time of this work. IB and SL are employees of and hold stock/stock options in Biogen. PW received funding for travel and honoraria (for lectures and advisory boards) from Biogen, Celgene/BMS, Janssen-Cilag, Merck, Novartis, Roche, Sandoz, Sanofi-Genzyme, and Teva.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Biogen.

ORCID iD

Sandra Vukusic

References

National Institute of Health. Multiple sclerosis, https://www.nccih.nih.gov/health/multiple-sclerosis (2019, accessed 23 January 2023).

McGinley

Goldschmidt

Rae-Grant

. Diagnosis and treatment of multiple sclerosis: A review. JAMA 2021; 325: 765–779.

Montgomery

Hillert

Bahmanyar

. Hospital admission due to infections in multiple sclerosis patients. Eur J Neurol 2013; 20: 1153–1160.

Tur

Dubessy

Otero-Romero

, et al. The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021. Mult Scler 2022; 28: 1424–1456.

Luna

Alping

Burman

, et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab and injectable therapies. JAMA Neurol 2020; 77: 184–191.

Brand

Smith

Piehl

, et al. Risk of serious infections in multiple sclerosis patients by disease course and disability status: Results from a Swedish register-based study. Brain Behav Immun Health 2022; 22: 100470.

Reyes

Ramsay

Ladhani

, et al. Protecting people with multiple sclerosis through vaccination. Pract Neurol 2020; 20: 435–445.

Riva

Barcella

Benatti

, et al. Vaccinations in patients with multiple sclerosis: A Delphi consensus statement. Mult Scler 2021; 27: 347–359.

Yap

Al Hinai

Gaughan

, et al. Vaccine hesitancy among people with multiple sclerosis. Mult Scler Relat Disord 2021; 56: 103236.

10.

Briggs

FBS

Mateen

Schmidt

, et al. COVID-19 vaccination reactogenicity in persons with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2022; 9: e1104.

11.

Simpson-Yap

De Brouwer

Kalincik

, et al. Associations of disease-modifying therapies with COVID-19 severity in multiple sclerosis. Neurology 2021; 97: e1870–e1885.

12.

Sormani

Salvetti

Labauge

, et al. DMTs and Covid-19 severity in MS: A pooled analysis from Italy and France. Ann Clin Transl Neurol 2021; 8: 1738–1744.

13.

Sormani

De Rossi

Schiavetti

, et al. Disease-modifying therapies and coronavirus disease 2019 severity in multiple sclerosis. Ann Neurol 2021; 89: 780–789.

14.

Polack

Thomas

Kitchin

, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020; 383: 2603–2615.

15.

Baden

El Sahly

Essink

, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021; 384: 403–416.

16.

Bsteh

Gradl

Heschl

, et al. Impact of vaccination on COVID-19 outcome in multiple sclerosis. Eur J Neurol 2022; 29: 3329–3336.

17.

Ciotti

Valtcheva

Cross

. Effects of MS disease-modifying therapies on responses to vaccinations: A review. Mult Scler Relat Disord 2020; 45: 102439.

18.

Bar-Or

Calkwood

Chognot

, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology 2020; 95: e1999–e2008.

19.

Bsteh

Hegen

Traxler

, et al. Comparing humoral immune response to SARS-CoV2 vaccines in people with multiple sclerosis and healthy controls: An Austrian prospective multicenter cohort study. Eur J Neurol 2022; 29: 1538–1544.

20.

Sabatino

Jr. Mittl

Rowles

, et al. Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function. JCI Insight 2022; 7: e156978.

21.

Achiron

Mandel

Dreyer-Alster

, et al. Humoral immune response in multiple sclerosis patients following PfizerBNT162b2 COVID19 vaccination: Up to 6 months cross-sectional study. J Neuroimmunol 2021; 361: 577746.

22.

Apostolidis

Kakara

Painter

, et al. Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy. Nat Med 2021; 27: 1990–2001.

23.

Garjani

Patel

Bharkhada

, et al. Impact of mass vaccination on SARS-CoV-2 infections among multiple sclerosis patients taking immunomodulatory disease-modifying therapies in England. Mult Scler Relat Disord 2022; 57: 103458.

24.

Schiavetti

Cordioli

Stromillo

, et al. Breakthrough SARS-CoV-2 infections in MS patients on disease-modifying therapies. Mult Scler 2022; 28: 2106–2111.

25.

Sormani

Schiavetti

Inglese

, et al. 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. EBioMedicine 2022; 80: 104042.

26.

National Multiple Sclerosis Society. Living well with MS, https://www.nationalmssociety.org/Living-Well-With-MS/Diet-Exercise-Healthy-Behaviors/Vaccinations (2022, accessed 29 June 2022).

27.

Farez

Correale

Armstrong

, et al. Practice guideline update summary: Vaccine-preventable infections and immunization in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2019; 93: 584–594.

28.

Otero-Romero

and on Behalf of the Working Group for the ECTRIMS-EAN European Consensus on Vaccination in MS Patients. Recommended standards for vaccinations in MS patients. Presented at ECTRIMS 2021. Mult Scler 2021; 27: 122.

29.

National Institute of Health and Care Excellence. Multiple sclerosis in adults: Management, https://www.nice.org.uk/guidance/ng220/resources/multiple-sclerosis-in-adults-management-pdf-66143828948677 (2022, accessed 13 August 2022).

30.

Multiple Sclerosis International Federation. MS, COVID-19 and vaccines – updated global advice, https://www.msif.org/news/2020/02/10/the-coronavirus-and-ms-what-you-need-to-know/ (2020, accessed 29 June 2022).

31.

Wiendl

Gold

Berger

, et al. Multiple Sclerosis Therapy Consensus Group (MSTCG): Position statement on disease-modifying therapies for multiple sclerosis (white paper). Ther Adv Neurol Disord 2021; 14: 17562864211039648.

32.

Lebrun

Vukusic

, French Group for Recommendations in Multiple S , et al. Immunization and multiple sclerosis: Recommendations from the French multiple sclerosis society. Mult Scler Relat Disord 2019; 31: 173–188.

33.

Naismith

Wundes

Ziemssen

, et al. Diroximel fumarate demonstrates an improved gastrointestinal tolerability profile compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: Results from the randomized, double-blind, phase III EVOLVE-MS-2 study. CNS Drugs 2020; 34: 185–196.

34.

Wehr

Hard

, et al. Relative bioavailability of monomethyl fumarate after administration of ALKS 8700 and dimethyl fumarate in healthy subjects. Neurology 2018; 90: P1–403.

35.

Mills

Ogrodnik

Plave

, et al. Emerging understanding of the mechanism of action for dimethyl fumarate in the treatment of multiple sclerosis. Front Neurol 2018; 9: 5.

36.

Gold

Arnold

Bar-Or

, et al. Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results. Mult Scler 2022; 28: 801–816.

37.

Naismith

Wolinsky

Wundes

, et al. Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study. Mult Scler 2020; 26: 1729–1739.

38.

Longbrake

Mao-Draayer

Cascione

, et al. Dimethyl fumarate treatment shifts the immune environment toward an anti-inflammatory cell profile while maintaining protective humoral immunity. Mult Scler 2021; 27: 883–894.

39.

Mehta

Miller

Arnold

, et al. Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice. Neurology 2019; 92: e1724–e1738.

40.

Smith

Calabresi

Bhargava

. Dimethyl fumarate treatment alters NK cell function in multiple sclerosis. Eur J Immunol 2018; 48: 380–383.

41.

Smith

Martin

Calabresi

, et al. Dimethyl fumarate alters B-cell memory and cytokine production in MS patients. Ann Clin Transl Neurol 2017; 4: 351–355.

42.

Moser

Seiberl

Feige

, et al. Tetravalent influenza vaccine is not associated with neuroaxonal damage in multiple sclerosis patients. Front Immunol 2021; 12: 718895.

43.

von Hehn

Howard

Liu

, et al. Immune response to vaccines is maintained in patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2018; 5: e409.

44.

Jaber

Patel

Sylvester

, et al. COVID-19 Vaccine response in people with multiple sclerosis treated with dimethyl fumarate, diroximel fumarate, natalizumab, ocrelizumab, or interferon Beta therapy. Neurol Ther 2023; 12: 687–700.

45.

Cohen

Bermel

Grossman

, et al. Immunoglobulin G immune response to SARS-CoV-2 vaccination in people living with multiple sclerosis within multiple sclerosis partners advancing technology and health solutions. Mult Scler 2022; 28: 1131–1137.

46.

Pitzalis

Idda

Lodde

, et al. Effect of different disease-modifying therapies on humoral response to BNT162b2 vaccine in Sardinian multiple sclerosis patients. Front Immunol 2021; 12: 781843.

47.

Wang

Shen

, et al. Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: A meta-analysis. EBioMedicine 2022; 81: 104102.

48.

Tallantyre

Vickaryous

Anderson

, et al. COVID-19 vaccine response in people with multiple sclerosis. Ann Neurol 2022; 91: 89–100.

49.

Schwarz

Mzoughi

Lozano-Ojalvo

, et al. T cell immunity is key to the pandemic endgame: How to measure and monitor it. Curr Res Immunol 2022; 3: 215–221.

50.

Baba

Ozcelik

Kaya

, et al. Three doses of COVID-19 vaccines in multiple sclerosis patients treated with disease-modifying therapies. Mult Scler Relat Disord 2022; 68: 104119.

51.

Maniscalco

Liotti

Ferrara

, et al. Humoral efficacy of the third SARS-CoV-2 vaccine dose in multiple sclerosis subjects undergoing different disease-modifying therapies. Mult Scler Relat Disord 2022; 68: 104371.

52.

Torres

Sancho-Saldana

Gil Sanchez

, et al. A prospective study of cellular immune response to booster COVID-19 vaccination in multiple sclerosis patients treated with a broad spectrum of disease-modifying therapies. J Neurol 2023; 270: 2380–2391.

53.

Etemadifar

Nouri

Pitzalis

, et al. Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: A practical review and meta-analysis. J Neurol Neurosurg Psychiatry 2022; 93: 986–994.

54.

Witman Tsur

Adrian Zaher

Tsur

, et al.

Current immunological and clinical perspective on vaccinations in multiple sclerosis patients: Are they safe after all?

Int J Mol Sci 2021; 22: 3859.

55.

Papeix

Mazoyer

Maillart

, et al.

Multiple sclerosis: Is there a risk of worsening after yellow fever vaccination?

Mult Scler 2021; 27: 2280–2283.

56.

Huttner

Eperon

Lascano

, et al. Risk of MS relapse after yellow fever vaccination: A self-controlled case series. Neurol Neuroimmunol Neuroinflamm 2020; 7: e726. doi:10.1212/NXI.0000000000000726

57.

Ciampi

Uribe-San-Martin

Soler

, et al. Safety and humoral response rate of inactivated and mRNA vaccines against SARS-CoV-2 in patients with multiple sclerosis. Mult Scler Relat Disord 2022; 59: 103690.

58.

Achiron

Dolev

Menascu

, et al. COVID-19 vaccination in patients with multiple sclerosis: What we have learnt by February 2021. Mult Scler 2021; 27: 864–870.

Vaccine response in people with multiple sclerosis treated with fumarates

Abstract

Keywords

Introduction

Vaccination in patients with MS

Vaccine response with DMTs

Effects of fumarates on immune response and vaccine response

Mechanisms of action and immunological effects of fumarates in patients with MS

Response to vaccines in patients with MS receiving fumarates

Response to COVID-19 vaccines in patients with MS receiving fumarates

Safety of vaccination in patients with MS treated with fumarates

Summary

Footnotes

Acknowledgements

Author contributions

Declaration of conflicting interests

Funding

ORCID iD

References