FormalPara Key Summary Points

People with multiple sclerosis (MS) may be at increased risk for infection, which can lead to relapses or pseudo-relapses.

Vaccines are an important health measure to prevent infections and require activation of humoral and cellular immune responses.

Some disease-modifying therapies (DMTs) for MS—including sphingosine-1-phosphate receptor modulators, which sequester lymphocytes from circulation; alemtuzumab (anti-CD52); anti-CD20 therapies; and cladribine (impairs DNA synthesis)—exert effects on humoral and cellular immune activity that may affect the response to available and emerging coronavirus disease 2019 (COVID-19) vaccines.

Coordinated interactions between T and B lymphocytes of the adaptive immune system are integral to the successful generation of immunological memory and the production of neutralizing antibodies.

Risks versus benefits of timing vaccinations to ensure maximum vaccine efficacy, as outlined in vaccination guidance and guidelines developed by national and international MS groups, should be considered in the decision to receive a COVID-19 vaccine—even if efficacy may be compromised—when disease burden is high.

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Multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disease of the central nervous system that causes significant and irreversible neurological disability [1, 2]. An estimated 2.8 million people are living with MS worldwide, including almost 1 million people in the USA; global prevalence in 2020 was 35.9 per 100,000 persons and is expected to rise [3, 4]. Although the etiology of MS is unknown, a number of environmental, genetic, and epigenetic factors are believed to contribute to immunopathogenesis of MS [5].

People with MS are at increased risk for acquiring certain types of infections, including respiratory and other viral and bacterial infections [6,7,8]. Additionally, certain disease-modifying therapies (DMTs), which suppress or alter the immune system, have been associated with increased risk of upper respiratory tract infections, urinary tract infections, and other infections [9]. This is relevant for people with MS because bacterial and viral infections have been shown to be associated with new or worsening baseline MS symptoms in the form of relapses or pseudo-relapses [10]. Upper respiratory tract infections can double the risk for relapse [11]. Furthermore, increased rates of influenza in the general population are temporally associated with a greater occurrence of relapses in people with MS [12]. It is speculated that relapses associated with an infection can be more neurologically damaging than those unrelated to infection [13]. Therefore, measures to prevent infection are particularly important for people with MS.

Over the years, there have been numerous iterations of consensus statements regarding the risks and benefits of vaccination in people with MS [14,15,16,17,18,19,20]. National and international guidance and guidelines generally agree that the benefits of vaccination outweigh any potential risks. The only exception is with live attenuated vaccines, which should not be used in people who are currently receiving or have recently discontinued immunosuppressive or immunomodulating DMTs, unless the risk of infection is elevated and nonlive vaccines are not available. The reason for this is that a live virus or bacteria has the potential to cause an infection and if the vaccine is administered during treatment with a MS DMT, the ability of the immune response to clear the infection could be impaired, which could possibly result in worsening of MS symptoms. Some DMTs exert effects on humoral and cellular immune activity that may affect the response to vaccination [21, 22].

Data on the efficacy of vaccinations in people with MS receiving immunosuppressive or immunomodulatory DMTs are still lacking, leading to a great deal of variability at the local, national, and international level with regard to vaccine guidance and guidelines [15,16,17, 19]. A better understanding of how DMTs for MS may influence vaccine safety and efficacy has become even more urgent given the current coronavirus disease 2019 (COVID-19) pandemic and recent authorization of vaccines specific for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19.

The incidence of COVID-19 in people with MS ranges from below 1% to 11% (including suspected but not confirmed cases) in studies that included a cross-sectional mixed method study, retrospective cohort analysis, and a prospective observational cohort study compared with World Health Organization (WHO) estimates of 1432 per 100,000 globally, and 8424 per 100,000 in the USA in the general population [23,24,25,26]. COVID-19-related MS mortality has been reported to be approximately 1–4% overall (compared with a case–fatality ratio in the general population of 0.0–9.2% in the 20 countries most affected by COVID-19, including the USA, which has a rate of 1.8% [according to Johns Hopkins University]), and more than 50% of deaths have occurred in people not receiving MS DMTs [27,28,29]. An analysis of data in people with MS from 28 countries who had suspected or confirmed COVID-19 found that treatment with ocrelizumab or rituximab was associated with significantly increased risk of hospitalization and admission to the intensive care unit compared with other pooled DMTs (including alemtuzumab, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate, interferon, natalizumab, and teriflunomide) [30]. Rituximab was also associated with significantly increased risk of artificial ventilation [30]. In a recent retrospective study from electronic health records, interferons and glatiramer acetate were shown to be associated with reduced COVID-19 risk, whereas anti-CD20 therapies were associated with increased risk, within the treated MS cohort [31]. In contrast, an analysis of COViMS registry data from 1626 patients with MS found that poorer clinical COVID-19 outcomes (including mortality) were associated with older patient age and greater disability whereas use of rituximab was associated with increased risk of hospitalization [32]. These findings suggest that the use of these anti-CD20 agents could be a risk factor for more severe infection.

Up to 98% of neurologists surveyed were concerned about their patients with MS contracting COVID-19, and 80% thought that certain DMTs would not permit a protective response to a COVID-19 vaccine [33]. Clinicians were most concerned about vaccine response and concomitant treatment with ocrelizumab (84%), rituximab (83%), and alemtuzumab (78%) [33], suggesting that prolonged T and B cell depletion is an important consideration. However, there may be an optimal timing of vaccination with some DMTs in order to achieve the best vaccine immune response.

This review will discuss the immune system, immunological effects of vaccination, existing data on the effects of DMTs on vaccination efficacy, and vaccine considerations in people with MS as they relate to currently available and emerging COVID-19 vaccines. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

The Immune System

The immune system is composed of two arms: the innate system and the adaptive or acquired system. It is the complex interplay between these two arms that comprises the normal immunological response to foreign antigens. The innate immune system is the first line of defense against infection; it plays a crucial role in the initial recognition of pathogens and in the activation of the cells of the adaptive immune system. Cells that are involved in innate immune responses include monocytes/macrophages, dendritic cells, mast cells, neutrophils, eosinophils, natural killer cells, and natural killer T cells [34]. These cells express receptors such as pattern recognition receptors, which are not specific to any particular pathogen and allow the cells to react to microbes containing common molecular structures, and pathogen-associated molecular patterns, including liposaccharides, other bacterial cell wall components, and virus-derived double-stranded RNA [35]. Innate immune responses occur more rapidly than adaptive immune responses and are generated within minutes to hours of infection [36]. However, subsequent encounters with the same pathogen will not elicit a faster or stronger response (i.e., no innate immunological memory is created) [36].

The Adaptive Immune System

The adaptive immune system is activated 4–7 days after exposure to a pathogen [37] in response to interactions between antigens, antigen receptor-bearing lymphocytes (T cells), and antigen-presenting cells (APCs); the lattermost can be specific cells of the innate immune system or B cells (Fig. 1) [37, 38]. The coordinated interactions between T and B lymphocytes of the adaptive immune system are integral to the immune system’s response when called into action by the innate immune cells [39]. Both T and B cells express unique antigen-binding receptors on their cell membranes [35]. Each cell expresses a single type of receptor and has the ability to rapidly proliferate and differentiate when activated.

Fig. 1
figure 1

Immune response to vaccination. a Occurs in multiple steps: (1) An APC (e.g., dendritic cells, macrophage, or B cell) recognizes vaccine antigen, resulting in local inflammation; and internalizes, processes, and presents antigen to CD4+ T cell in MHC class II. (2) Antigen-specific T cell becomes activated, differentiates, and secretes cytokines to support B cell activation. B cells become activated via interaction with T cells (contact-dependent or contact-independent [involving cytokines]) and differentiate into plasma cell/plasma blast, which produces neutralizing antibodies that can prevent future infection. T (CD4+ and CD8+) and B cells proliferate, but dendritic cells become limited to support continued differentiation. B cells take over to help continued differentiation and proliferation of T cells by providing late co-stimulatory signals and secretion of cytokines/survival signals that enhance T cell memory formation. (3) Optimal immune memory results (i.e., more memory CD8+ T cells, better survival, and enhanced cytotoxicity). Approximately 10% of activated B and T cells become memory cells to help prevent disease in the future. Without B cells, suboptimal memory results (fewer cells, poor survival, and decreased cytotoxicity in cells that remain). b B and T cell interactions are bidirectional and form an integral part of the immune response to vaccination. APC antigen-presenting cell, MHC major histocompatibility complex

Cellular Response

T cells mediate the cellular immune response [40,41,42]. They are activated by APCs that have digested an antigen and are displaying a peptide from the antigen on their membrane (bound by major histocompatibility complex molecules) [35]. Specific subtypes of T cell are produced and have differentiated functions, including CD8+ (cytotoxic T cells), CD4+ (helper T cells), and follicular T helper cells, among others [40]. CD8+ T cells reduce, control, and eliminate intracellular pathogens by directly (via release of perforin, granzyme, etc.) or indirectly (via antimicrobial cytokine release) killing infected cells [40]. CD4+ T cells are involved in the reduction, control, and clearance of extracellular and intracellular pathogens. This occurs through the release of cytokines that support the activation and differentiation of B cells, CD8+ T cells, and macrophages, contributing to defense against bacteria and viruses on mucosal surfaces [40]. Subsets of CD4+ T cells include T helper 1, 2, 9, and 17 cells; regulatory T cells; and, as mentioned previously, follicular T helper cells [43], which provide an intricate and highly specific response to the pathogen.

Humoral Response

The cellular immunity that is achieved by the differentiation and production of antigen-specific T cell populations is important, but it is only one part of the adaptive immune response. The other part is humoral immunity, which is composed of B cells, the complement system, and antibodies [38, 40, 44].

B cells are activated by cytokines released by T helper cells (e.g., interleukin [IL]-4, IL-5, IL-5, IL-13) and upon activation differentiate into plasma cells, which produce antibodies [37, 40, 45]. B cells can also recognize antigens directly, without the involvement of APCs of the innate immune system [35]. Antibodies stop or reduce infections via clearance of extracellular pathogens through binding to the enzymatic active sites of toxins or preventing their diffusion, by neutralizing viral cell entry, promoting phagocytosis of extracellular bacteria, and activating the complement cascade [40]. Additionally, B cells play a role in the further activation of T cells and are involved in both antigen presentation to T cells and the generation of immunological memory [46]. Immunological memory is the capability of the immune system to respond more quickly and effectively to pathogens encountered earlier, and is based on persistent populations of clonally expanded, specialized memory T and B cells [37]. Complement factors opsonize antigens, which can then stimulate the complement receptor 2 expressed on B cells and lower the threshold for producing neutralizing antibodies [44].

Vaccine-Related Immune Response

Vaccines exert their effects through the immune system and rely on both the innate and adaptive arms interacting in a complex and complementary fashion with the goal of generating immunological memory [35]. A variety of vaccine types exist, as shown in Table 1, and they elicit varying degrees of long-term immunological response.

Table 1 Types of vaccines

In response to vaccination, the innate, humoral (B cell mediated), and cellular (T cell mediated) immune pathways are activated through multiple steps (Fig. 1) [42, 45]. Initially, inflammation occurs at the site of administration, which can be intramuscular, subcutaneous, oral, or pulmonary/nasal, and is followed by activation of the innate system [45, 63]. The site of administration can affect the immune response [64]. For example, immunization via parenteral administration can fail to induce mucosal immunity [63], while pulmonary/nasal administration of experimental nanoparticle vaccination has resulted in high-frequency, long-lasting, antigen-specific effector memory T cell response at mucosal sites and increased antigen transport [65].

Following vaccine administration, the delivery of vaccine antigens by APCs to activate and recruit CD4+ T cells results in T and B cell interaction and the first step of the antibody response: B cell proliferation, maturation, and differentiation into plasma cells [40, 45]. However, the resulting antibodies have low affinity for the antigen, and the response is short-lived. This is followed by the effector phase of the response, which involves the production of higher-affinity antibodies by B cells, differentiation and proliferation of effector T cells [40], and generation of immunological memory, allowing a more rapid and efficient response when the target pathogen is encountered at a later time [37]. B cells are then involved in modulating the contraction of CD8+ T cell responses following immunization and in generating memory T cells [46]. Follicular T helper cells are integral to B cell activation or differentiation into memory and plasma cells and in the generation of long-lived antibody responses [66]. The role of follicular T helper cells in the response to vaccination is especially important in the context of therapies for MS that alter or deplete certain immune cell populations. If the follicular T helper cell response is suppressed, complete seroprotection is unlikely to be achieved with a vaccine or even repeated vaccination. Nevertheless, partial seroprotection could still be enough to prevent contracting the infection of interest and/or preventing severe complications from the infection.

The US Centers for Disease Control and Prevention frequently updates the recommendations for adults receiving routine vaccinations to prevent 17 vaccine-preventable diseases [67]. Recommendations are made on the basis of the effectiveness of the vaccines, which is assessed by humoral response (i.e., the presence of antigen-specific antibody titers) [68]. The hemagglutination inhibition assay, which measures the presence of antibodies to hemagglutinins (which are glycoproteins on the surface of influenza viruses), is one way to measure influenza vaccine response [68, 69]. Typical outcomes seen in clinical trials for vaccines include assessment of antibody titers, seroconversion rates, seroprotection rates (percentages of people developing neutralizing antibodies), functional antibodies (by flow cytometric opsonophagocytosis assays), antibody avidity, B cell and T cell activation, lymphoproliferation, and cytokine responses [70].

However, systems for measuring cellular responses to vaccination are not typically utilized in clinical trials or clinical practice for a number of reasons, including the complexity and cost associated with such assays. For example, US Food and Drug Administration guidelines for influenza vaccine development rely on hemagglutination-inhibiting (HI) antibody titers, i.e., percentage of subjects achieving an HI antibody titer of at least 1:40 and rates of seroconversion (change in titer from less than 1:10 to at least 1:40 or fourfold rise in HI antibody titer) [71]. T cells have been demonstrated to play a role in the immune response to SARS-CoV-2 [72, 73], but such responses are difficult to measure, which has prevented a full understanding of the role of T cells in an effective vaccine response against SARS-CoV-2. Because these data on cellular responses to vaccination are limited, the extent to which any one individual or group of individuals responds to vaccination is difficult to ascertain. In the future, systems biology may be used to analyze early human immune responses to vaccination. Using such approaches, individuals who have been vaccinated may display noticeable and characteristic changes in the gene expression profiles of their peripheral blood leukocytes, allowing for an understanding of the immune response beyond just antibody titers [74].

As treatment of MS evolves toward a personalized approach, immune correlates and how vaccine response is measured—including not only humoral immune responses but also cellular immune responses—may help determine the true differential impact of MS DMTs on vaccine immune response. Moreover, the management of MS may prove to be an incremental burden revolving around treatment choices and timing, if a yearly COVID-19 vaccine or booster becomes necessary.

Individuals may experience diminished protection from vaccines for various reasons. For example, inadequate responses have been reported in people aged over 64 years [75], which may result from immunosenescence stemming from thymic involution, a decrease in naïve T cells, increased T cell memory defects, and impaired ability of B cells to undergo class-switch recombination (i.e., isotype switching), resulting in less diversity of antibodies and decreases in naïve B cells [76]. Other factors that may affect response include sex, obesity, behavior, comorbidities, pregnancy, immunosuppression, and possibly ethnicity [70, 77, 78]. All of these considerations will apply to people with MS as well, and may impact vaccine responsiveness in this population.

Guidance and Guidelines on Vaccines from MS-Related Societies and Organizations

A number of organizations have made recommendations regarding vaccination for people with MS (Table 2) and, importantly, most point to the lack of high-quality data that can support recommendations [16,17,18]. The only recommendation by the American Academy of Neurology (AAN) based on the strongest level of evidence (level A) is to screen for certain infections, according to the prescribing information of the particular immunosuppressive or immunomodulating DMT being considered as treatment, and for latent infections in high-risk populations or in countries where specific infections are common [16].

Table 2 Vaccine guidance and guidelines for people with MS

A Delphi consensus statement from a panel of experts and the French Multiple Sclerosis Society (Société Francophone de la Sclérose en Plaques) agree with AAN regarding limited studies; and the French Multiple Sclerosis Society recommendations regarding preventative methods are generally similar to those of AAN [17, 18]. The National Multiple Sclerosis Society and Multiple Sclerosis Association of America currently reference AAN and US Centers for Disease Control and Prevention guidance and guidelines and use language from DMT product labels regarding vaccination recommendations [15, 20].

Although robust data to support evidence-based recommendations on COVID-19 vaccinations are not yet available, the Multiple Sclerosis International Federation and the National Multiple Sclerosis Society have recently advised vaccination for most people with MS, which can occur while treatment with DMTs is ongoing [14, 19, 79]. Both have also recently made recommendations regarding the timing of DMTs with COVID-19 vaccination (Table 2) [19, 80].

These COVID-19 vaccination guidance and guidelines are living documents based on what has been learned from previous vaccine studies, DMT prescribing information, ongoing studies and registries such as the COViMS registry, and expert consensus, and will be updated over time as more data become available and as more vaccines are approved for use.

Vaccine Efficacy and DMTs

Because DMTs have immunosuppressive and/or immunomodulating effects, data on vaccination efficacy in people with MS treated with DMTs may help inform how the immune response may be impacted and whether there should be considerations about optimal timing of vaccine administration with DMTs. Most reports have been on the response to influenza vaccination. People with MS are able to mount a cellular immune response following influenza vaccination [83]. However, increases in influenza-specific T cells following vaccination are higher in people with MS than in healthy controls and, importantly, no increases in T cell responses to central nervous system myelin proteins (i.e., human myelin basic protein or recombinant human myelin oligodendrocyte protein) were seen [83]. A meta-analysis of studies on influenza vaccination in patients with MS found no statistical difference in immune responses versus healthy controls and that most immunotherapies did not affect the immune response [84].

As previously mentioned, the different mechanisms of action for DMTs (summarized in Table 3) have been shown to impact immune responses to vaccination with administration of different DMTs. This has been demonstrated in clinical studies, case reports, and some preclinical data (Table 4). Several reports on interferon beta products indicate that people with MS treated with interferon beta can generate protective levels of response to influenza, tetanus-diphtheria toxoid, pneumococcal vaccine polyvalent, and meningococcal vaccines [85,86,87,88,89,90], with no evidence for a reduction in tetanus toxoid-induced T cell responses [91]. Endogenous interferon betas are part of the type I interferon family, which play an important role in antiviral response [92, 93]. The binding of interferons to their receptors causes a signaling cascade leading to upregulation of genes that results in production of antiviral molecules such as myxovirus resistance proteins, adenosine deaminase acting on RNA (ADAR1), oligoadenylate synthetase, and RNase L nuclease [93,94,95,96]. Postmarketing surveillance data showing no increased risk of infection suggest therapeutic interferon betas may have some protective antiviral effects [97].

Table 3 DMTs and vaccination recommendations for people with MS
Table 4 Studies on effect of DMTs on response to vaccination

For all other DMTs, data suggest a diminished immune response to vaccination, usually influenza vaccination. Glatiramer acetate may also impact the immune response, though most studies indicate adequate responses [87, 130, 131]; in one study, patients on glatiramer acetate had slightly lower responses to influenza vaccination compared with healthy controls [90]. Teriflunomide was found to cause a mild dose-dependent reduction in the efficacy of influenza and rabies vaccines [86, 134]; higher doses of teriflunomide induced a lower response to at least one strain of influenza in the vaccines [86].

Among sphingosine-1-phosphate (S1P) receptor modulators, most data were available for fingolimod. Patients treated with fingolimod had reduced response rates to influenza vaccination versus patients treated with interferon or placebo or versus healthy controls and no increase in avidity (binding) of influenza-specific immunoglobulin (Ig) G was seen [87, 130, 136, 137]. Studies and case reports also indicate that fingolimod affected responses to varicella zoster and pneumococcal polysaccharide vaccines [138,139,140,141]. The few data available for the other S1P receptor modulators, including a pooled analysis of two trials of ozanimod (n = 2659), suggest similar reductions in responses to vaccination [145, 146].

A study on dimethyl fumarate found adequate seroprotection and no reduction in immune responses to tetanus toxoid, pneumococcal polysaccharide, or meningococcal vaccines compared with interferon [85]. In addition, in the 96-week PROCLAIM study, antibody (IgA, IgG, IgM, and IgG1–4) subclass levels were stable with long-term (96-week) dimethyl fumarate treatment, though lymphocyte levels decreased (i.e., naïve CD4+ and CD8+ T cell increases, CD4+ and CD8+ central and effector memory T cell decreases) [152]. This indicated a shift from an inflammatory to an anti-inflammatory cell profile without impairment of humoral immunity [152]. No data were available for the other fumarates.

Some information was available for several high-efficacy DMTs in people with MS. A randomized controlled study in patients with MS treated with natalizumab showed that all evaluated patients achieved protective levels of anti-tetanus toxin IgG antibodies, and a slightly lower proportion of responders to primary immunization with keyhole limpet hemocyanin with natalizumab compared to control group, suggesting that natalizumab may not significantly influence responses to primary or secondary immunization [147]. In several small studies, patients with MS treated with natalizumab achieved either comparable or lower responses to influenza vaccination versus those treated with interferons or versus healthy controls depending on the strain [87, 90, 130]. Although the studies were limited by small sample sizes with no adjustment for disease factors in the patients with MS, the responses were generally considered more than adequate to achieve seroprotection.

In a large study in patients with MS (N = 102), those treated with ocrelizumab were found to have substantially impaired responses to tetanus toxoid, influenza, and pneumococcal vaccines and to the neoantigen keyhole limpet hemocyanin compared with controls on interferon beta or no DMT [149]. Despite these attenuated immune responses, patients still mounted a humoral response, and the authors concluded that an adequate vaccine response is generated after ocrelizumab treatment that is seroprotective [149]. On the basis of these data, there may be an optimal timing of vaccine administration with this DMT. In phase 3 trials, patients with MS treated with ocrelizumab also experienced decreases in IgG and IgM antibodies below the lower limit of normal 96–120 weeks after starting treatment with ocrelizumab, which is predictable on the basis of the mechanism of action of this therapy [123]. A single case report of loss of vaccinal immunity against varicella zoster virus suggests that ocrelizumab may impair varicella vaccines; however, this finding needs to be replicated in a larger cohort [150].

Interest in off-label treatment with rituximab for MS has increased [153, 154], but vaccination studies in patients with MS have not occurred to date. However, registry data (N = 822) show that 3% of patients with MS experience reductions in IgG below the lower limit of normal at some point during treatment [155]. Two systematic review and meta-analysis studies found a reduced response to pneumococcal vaccination [156, 157] and influenza vaccine [157] in patients with rheumatoid arthritis treated with rituximab but not for those who received anti-tumor necrosis factor alpha (TNFα) agent. Similarly, in a systematic review of studies in patients with rheumatoid arthritis or other inflammatory rheumatic diseases, rituximab also significantly decreased responses to an influenza vaccine, with tenfold lower hemagglutination inhibition assay titers observed in those administered rituximab less than 12 weeks before vaccination versus those administered rituximab more than 24 weeks before vaccination [158]. A second dose of the vaccine was needed to achieve responses comparable to those achieved with a single dose in healthy controls. No studies on vaccines are available for ofatumumab.

Data on alemtuzumab suggest vaccination should occur at least 6 months before starting treatment because depletion of T and B cells, as occurs with alemtuzumab treatment, would diminish response to vaccination [151].

The one study that included the DNA disrupter mitoxantrone reported an almost complete lack of response to influenza vaccination [90]. No studies on vaccines are available for cladribine.

COVID-19 Vaccine Trials and Considerations for People with MS

Multiple COVID-19 vaccines are in development [159] and a number are already being administered worldwide. Many target the spike protein of SARS-CoV-2, a protein expressed on the surface of the virus that facilitates entry into host cells, with the goal of generating robust humoral and T cell responses [160, 161]. This protein binds to a receptor on the host cell surface and then causes the virus and host cell membranes to fuse [53, 162].

Three vaccines, BNT162b2 (developed by Pfizer and BioNTech), mRNA-1273 (developed by Moderna), and Ad26.COV2.S (VAC31518; JNJ-78436735; developed by Janssen Biotech), have received emergency use authorization but have not yet received approval from the US Food and Drug Administration at the time of this publication [163,164,165]. BNT162b2, mRNA-1273, and another vaccine, ChAdOx1 nCoV-19 (AZD12222; developed by AstraZeneca and Oxford Vaccine Group), have received conditional marketing authorization in the European Union [166, 167]. BNT162b2 and mRNA-1273 contain lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the SARS-CoV-2 full-length spike protein but modified by two proline mutations [53, 168], and are administered in two doses [169]. Ad26.COV2.S (VAC31518; JNJ-78436735), administered in a single dose, and ChAdOx1 nCoV-19, administered in two doses, are recombinant replication-deficient adenovirus vector vaccines encoding the spike protein gene [57,58,59].

Efficacy and safety data for these vaccines are shown in Table 5. Adverse events reported for all the vaccines included local reactions, such as pain at the site of administration, and systemic reactions that included headache, fever, and fatigue. Bell’s palsy (n = 3) was reported with mRNA-1273 and facial paralysis (n = 2), brachial radiculitis (n = 1), Guillain–Barré syndrome (n = 1), transverse sinus thrombosis (n = 1); postvaccination syndrome (n = 1) was reported with Ad26.COV2.S (VAC31518; JNJ-78436735) [59, 170]. Another candidate of interest is NVX-CoV2373 (developed by Novavax), a subunit recombinant nanoparticle created from the spike protein [50, 51]. No efficacy data are available yet; however, a small study showed inducement of anti-spike antibody and T cell responses [51] (Table 5).

Table 5 Major COVID-19 vaccines in use or in development

Members of the MS community have expressed an interest in COVID-19 vaccination. A US online survey of people with MS in the spring of 2020, before any COVID-19 vaccines were available, found that approximately two-thirds of respondents were willing or moderately willing to be vaccinated [175]. However, analyses focusing specifically on MS subgroups have yet to occur, and it is unknown how many people with MS have participated in COVID-19 vaccine studies. Thus, current knowledge pertaining to COVID-19 vaccination in patients with MS is based on conventional vaccines and anecdotal experience in those who have received the vaccine thus far. The percentage of seroconversion that is deemed sufficient for “protection” varies on the basis of what the vaccine/pathogen is, and people receiving certain DMTs may be able to mount some, albeit diminished, antibody response to vaccination. Duration of disease may also affect response to vaccination. Longer disease duration (p = 0.040; odds ratio = 0.910) has been associated with an insufficient response to influenza vaccine in people with MS treated with interferons, glatiramer acetate, natalizumab, fingolimod, and other DMTs [87]. These findings may be impacted not only by DMT but also by age, comorbidities, and other factors.

When thinking about the potential impact of MS DMTs on vaccine efficacy, the role of specific immune cell populations may be considered. For example, T cell signatures may be a more sensitive measure of past SARS-CoV-2 infection than antibody assays, as individuals with symptomatic infections or who required hospitalization had higher T cell responses [176]. This suggests that disease-specific memory T cells, in addition to antibody titers, may be measurable and reliable correlates of protection [176]. However, SARS-CoV-2-reactive CD4+ T cells have been reported in 35–60% of unexposed individuals, suggesting possible cross-reactive T cell recognition between other coronaviruses (e.g., common cold viruses) and COVID-19 [177,178,179]; the protective effect of such cross-reactive T cells is unclear.

Coronavirus-specific T cells from Middle Eastern respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) have been shown to have long-term persistence and contribute to protection [176, 180, 181]. Hence, DMTs that deplete or significantly impact T cells may affect the efficacy of potential COVID-19 vaccines. Moreover, the National Multiple Sclerosis Society advises waiting at least 12 weeks after the last dose of B cell-depleting treatment before vaccinating [80], as anti-CD20 antibodies (i.e., ocrelizumab) have been found to induce rapid and prolonged (up to 24 weeks) B cell depletion and attenuated humoral immune responsiveness to vaccination in people with MS [149]. Many clinicians advise their patients that if given a choice, they should receive a vaccine when available and worry about timing later. More data are needed to fully understand the necessity of the memory B cell population, an important target of anti-CD20 therapies, to drive persistent antibody responses for extended periods of time following vaccination. Delaying therapy to allow for a more robust B cell response to the COVID vaccine, only to potentially diminish this response when therapy is resumed, may be counterproductive. Lastly, the impact that B cell-depleting therapies may have on other components of the immune system, including T cells, may also need to be a consideration for vaccine administration.

Because of their persistence (as opposed to declining levels of antibodies), T cells may be the more important measure for determining the efficacy of COVID-19 vaccines. However, antibodies still clearly have a role in preventing future infection through neutralization of a virus before it can infect a cell. Indeed, vaccines are traditionally designed to elicit a very robust humoral immune response, in addition to a cellular immune response, to convey both protection from infection and prevention of disease. The COVID-19 vaccines are not an exception to this. Moreover, even if antibody titers decline, this does not negate the fact that memory B cells should still be present and able to contribute significantly to the prevention of future infection, highlighting the importance of maintaining adequate levels of both B cells and T cells during the vaccination period and beyond [45].

Although the evidence clearly demonstrates the importance of measuring and generating a T cell or cell-mediated response to COVID-19 vaccines (as evidenced by the detection of SARS-CoV-2-specific T cells in convalescent patients [182]), it is important to remember that the immune response is a coordinated effort that must be orchestrated by both T cells and B cells (or cell-mediated and humoral immunity), as evidenced by the essential role that B cells have been shown to play in the generation of T cell memory [39, 183].


Infections can be associated with an increased risk of relapses or pseudo-relapses in people with MS. For this reason, vaccination is an important tool that should be utilized, whenever possible, to limit infection in this population. However, the use of DMTs, which alter various components of the immune response, may also reduce the vaccine immune response in people with MS. In light of the current COVID-19 global pandemic and the recent authorization of novel vaccines against COVID-19, a better understanding of how MS DMTs may alter the immune response to vaccination is greatly needed. This review highlights previous studies of vaccine response in people with MS and focuses on how immunological impairment driven by various DMTs may impact successful vaccination strategies against COVID-19 in this patient population.

Immunological studies have shown that the coordinated interactions between T and B lymphocytes of the adaptive immune system are integral to the successful generation of immunological memory and production of neutralizing antibodies, following recognition of vaccine antigens by innate immune cells. CD4+ T cells play an essential role in facilitating both CD8+ T cell and B cell activation, but the inverse is also true, with B cells playing an important role in driving and sustaining T cell memory.

Previous studies of the immune response to vaccines other than COVID-19 in people with MS receiving various DMTs (Table 2) have shed some light on the key question of how each DMT or class of DMTs might affect the efficacy of a COVID-19 vaccine. Indeed, the data suggest that type 1 interferons, glatiramer acetate, and possibly teriflunomide may not significantly impair the response to vaccination, as opposed to those DMTs that rely on sequestration or depletion of large populations of immune cells, including S1P receptor modulators, alemtuzumab, cladribine, and anti-CD20 therapies. Other factors that could impact vaccine efficacy, including age and comorbidities, are beyond the scope of this review but should be considered. Benefits of vaccination, as outlined in guidance and guidelines from national and international MS groups, should be considered—even if vaccine efficacy may be compromised—when disease burden is high.