SARS-CoV-2 Вакцины и множественный склероз: обновление.

Introduction

The coronavirus disease 2019 (COVID-19) pandemic has posed new challenges for humanity and the health care sector in particular. This was especially true for people with chronic diseases such as multiple sclerosis (MS) because it was unknown whether people with MS (PwMS) had an increased risk of becoming infected or suffering a more severe course of infection, particularly when being treated with disease-modifying therapies (DMTs). 5 The initially implemented general measures, including lockdowns, not only hampered health care for PwMS but also affected their working and social lives and ultimately their quality of life. 6 The emergency authorization of the first COVID-19 vaccine in December 2020 was the turnaround in the fight against the pandemic, namely vaccination, but also created again new challenges. 7 For PwMS in particular, the issue of vaccination and vaccine hesitancy is a hot topic that has been reinforced by the COVID-19 pandemic. 8 On top of this, there was uncertainty about the ideal timing of vaccination and the response to vaccination under treatment with different DMTs.

Owing to all these important aspects, the aim of this article was to first address the topic of vaccines in general, particularly regarding the new vector-based and mRNA-based vaccines. Subsequently, we want to take a closer look at the essential topic of vaccination skepticism regarding MS. Following this, the goal was to briefly answer the abovementioned questions concerning the risk of infection and a possible more severe course of a COVID-19 infection in relation to PwMS, particularly in the context of DMTs. We then review immune responses after both natural infection and vaccination and how they are affected by various DMTs. Finally, we strive to summarize the resulting key points in the form of recommendations to provide more clarity for clinical practice on this very important highly publicized issue.

SARS-CoV-2 Vaccines and Their Effectiveness

According to the World Health Organization (WHO), by March 30, 2023 (last update by the WHO), there are 382 SARS-CoV-2 vaccines in development, of which 199 are in the preclinical phase and 183 in the clinical phase (50 in phase III and 11 in phase IV). 9 A total of at least 64 different SARS-CoV-2 vaccines have already been approved in 201 countries, of which 7 are actually within the WHO Emergency Use Listing (WHO-EUL), resulting in the administration of over 13.6 billion vaccine doses worldwide to date. 2,10-13 Of note, by December 31, 2023, 67% of the world population has received at least a complete primary series of a COVID-19 vaccine while only 32% of people received at least one booster dose of a COVID-19 vaccine. 2

Former and current European Medicines Agency (EMA)–authorized SARS-CoV-2 vaccines are summarized in Table 1 . 14,15

Table 1 Overview of Former and Current European Medicines Agency–Authorized SARS-CoV-2 Vaccines Trade name Manufacturer Vaccine type EMA Current approval status by EMA Current EMA-authorized and adapted vaccines Comments Comirnaty BioNTech manufacturing GmbH mRNA Standard marketing authorization: 10/10/2022 √ Comirnaty KP.2–26/09/2024 Comirnaty JN.1–03/07/2024 Comirnaty Omicron XBB.1.5–31/08/2023 Therapeutic indication for primary vaccination and booster Spikevax Moderna Biotech Spain S. L mRNA Standard marketing authorization: 03/10/2022 √ Spikevax JN.1–10/09/2024 Spikevax XBB.1.5–15/09/2023 Therapeutic indication for primary vaccination and booster Nuvaxovid Novavax CZ, a.s Protein subunit Standard marketing authorization: 04/07/2023 √ Nuvaxovid JN.1–08/10/2024 Nuvaxovid XBB.1.5–31/10/2023 Therapeutic indication for primary vaccination and booster Bimervax HIPRA human health SL.U. Inactivated, adjuvanted Marketing authorization issued: 30/03/2023 √ Therapeutic indication only for booster Valneva Valneva Austria GmbH Inactivated, adjuvanted Marketing authorization: 24/06/2022 ⊗ Withdrawal of the marketing authorization: 12/10/2023 VidPrevtyn β Sanofi Pasteur Protein subunit Marketing authorization issued: 10/11/2022 ⊗ Withdrawal of the marketing authorization: 11/03/2024 Jcovden Janssen Cilag international NV Vector-based (nonreplicating) Standard marketing authorization: 09/01/2023 ⊗ Withdrawal of the marketing authorization: 09/08/2024 Vaxzevria AstraZeneca AB Vector-based (nonreplicating) Standard marketing authorization: 31/10/2022 ⊗ Withdrawal of the marketing authorization: 27/03/2024

Overview of Former and Current European Medicines Agency–Authorized SARS-CoV-2 Vaccines

These vaccines represent the most widely administered SARS-CoV-2 vaccines worldwide. 16 In addition, several inactivated and protein subunit vaccines as well as DNA-based, virus-like particle (VLP)–based, and (replicating) vector-based vaccines have already been licensed outside the European Union. 10 Noteworthy, the various authorized vaccination regimens (children and adolescents, adults, older individuals, and risk groups), including heterologous regimens regarding vaccine type, must always be performed in compliance with the requirements of the national/regional authorities.

Based on pivotal trials and postmarketing data, all EMA-approved vaccines demonstrated high efficacy. 17-22 Remarkably, high efficacy has been observed in particular for older individuals, who are at increased risk of severe/critical COVID-19, as well as for variants of concern (VOCs), although vaccine effectiveness is waning more rapidly in older individuals. 23-31 Protection against infection decreased 20%–30% by 6 months after full immunization, with a strong correlation between antibody titer and the likelihood of breakthrough infection. 32-37 In addition, data have been published showing that with increasing vaccine doses, lower antibody titers are required to protect against breakthrough infection (explained by antibody affinity maturation). 38 Nevertheless, particularly regarding VOCs, it has been shown that protection against SARS-CoV-2 infection weakens after 6 months. However, severe disease courses requiring admission to intensive care units (ICUs) still seem to be preventable. 39-45 Breakthrough infections seem to occur primarily in association with predispositions such as age, comorbidities, and immunosuppressive therapies and with VOCs. 23,31,46-48 However, compared with primary infections, they are associated with a better outcome and lower transmissibility. 49 , 50 , e3 Notably, vaccination shortens the duration of the high transmission potential and the duration of the symptomatic phase, and it may also limit tissue dissemination. 49 On this matter, a study from Israel showed that a second booster vaccination in adults aged 60 years or older significantly reduced hospitalizations and deaths due to COVID-19. e4 A recent study in the WHO European Region, where between December 2020 and March 2023, 2.2 million deaths from COVID-19 had been reported, estimated that with vaccination, the risk of deaths was reduced by 59%. Almost all lives saved were in the age range of 60 years or older, mostly in the first booster-receiving population and during the Omicron wave. e5 Nevertheless, vaccinations, infections, and hybrid immunity do not provide absolute protection, which is why adherence to nonpharmacologic regimens such as social distancing, quarantine, masking, and improved ventilation, especially indoors with crowded conditions and at the time of new infection waves, remains important. e6

SARS-CoV-2 Variants

SARS-CoV-2 variants can be differentiated into variants of (or under) monitoring (VOMs; VUMs), variants of interest (VOIs), and VOCs, the latter being most relevant. e7 -e9 VOCs and VOIs have been defined because of their ability to replace so far circulating variants and cause new waves of increased transmission, resulting in a need for adaption of public health policies. e10

Hence, the heat map in the Figure shows the evolution of VOCs over time, including Omicron sublines.

Heat Map on Evolution of VOCs and Omicron Sublines

Heat map showing the evolution of VOCs over time including Omicron sublines; Pango lineage names (e.g., B.1.351) are given, as well as the naming by using letters of the Greek alphabet for the 5 VOCs (Alpha, Beta, Gamma, Delta, Omicron)—the according predominat Delta variant has no Pango lineage naming. e1–e13 VOCs = variants of concern.

In this context, the SARS-CoV-2 variant B.1.1.529 (“Omicron”) was detected for the first time in South Africa on November 9, 2021, which was rapidly declared the fifth VOC by the WHO on November 26, 2021. e14 Since then, it has evolved very quickly into the globally predominant variant and represented up to 100% of the detected sequences, including its actual sublines. e7,e15-e18 Given the persistent global predominance of the Omicron variant, the definitions of VOIs and VOCs were adapted by the WHO to include Omicron subvariants as separate variants to be tracked. e10

Of note is the presence of over 30 variations in the spike glycoprotein, leading to higher viral fitness level and, therefore, persistent global dominance of Omicron and consecutively its sublines. e15,e19 According to a report from the United Kingdom, the hospitalization risk is reduced by 20%–25% compared with the B.1.617.2 variant (“Delta”), although it seems to be 10 times more contagious than the original virus and 2.8 times more infectious than the Delta variant. e20-e22 Similar observations have been reported from South Africa with fewer hospitalizations, more young patients without comorbidities affected, and much less acute respiratory conditions. e16,e23 Adequate, albeit significantly diminished, humoral protection against the Omicron variant seems to be present only in triple or more often vaccinated individuals or individuals with hybrid immunity (at least 2 vaccinations). e24-e33 In this context, it has been shown that the maturation of humoral immunity over time enhances the efficacy and breadth of antibodies against variants, including Omicron subvariants, after infection or vaccination, and this is further amplified by repeated vaccinations or infections. e34-e36 Therefore, in particular, people with hybrid immunity may receive a booster vaccination in an extended interval of 12 months regarding the last infection/vaccination to generate the most effective humoral immunity possible. e32,e37 So far, there does not seem to be a major T-cell immunity escape. e38-e43 By contrast, a rapid and potent T-cell response was obtained in breakthrough infections after previous vaccination. e44 Following this, the first T-cell immunity–directed COVID-19 vaccines are already being investigated in clinical trials, especially for patients with B-cell deficiency. e45

Finally, at the present time (November 2024), the KP.3 Omicron subvariant is the predominating variant worldwide, and the first preliminary results, concerning the authorized adapted (XBB.1.5) Comirnaty and Spikevax vaccines, indicate a promising humoral and cellular immune response regarding the prevalent Omicron subvariants. e46-e48

SARS-CoV-2 Vaccines: Safety

Regarding safety, besides the classical local and systemic postvaccinal reactions, several studies have reported the rare occurrence of autoimmune disorders such as myocarditis or pericarditis after vaccination with Comirnaty and Spikevax. e49-e54 In the latest specific update from the EMA's safety committee (Pharmacovigilance Risk Assessment Committee [PRAC]) dated December 3, 2021, reference is made to the package insert, where this risk is clearly mentioned. It is also noted that this is a rare side effect that occurs in up to 1 in 10,000 vaccinated individuals, preferably in young men, and after the second vaccination and mostly within the first 14 days after vaccination based on 2 major studies. e55-e58 Hence, clinicians, as well as PwMS, should be alerted to the possible symptoms of myocarditis and pericarditis (e.g., chest pain, shortness of breath, and palpitations), after mRNA-based vaccination. e58 This must be contrasted by the clearly higher risk of myocarditis after SARS-CoV-2 infection than after SARS-CoV-2 vaccination, shown by an incidence risk ratio of 11.14 and even 14.87 in people aged 40 years or older. e59

Furthermore, the EMA reported that vaccine-induced thrombotic thrombocytopenia (VITT) can occur in up to 1 in 10,000 cases after vaccination with Vaxzevria or Jcovden. e60,e61 In an international network cohort study, a 30% increased risk of thrombocytopenia after the first dose of Vaxzevria and a trend toward an increased risk after Jcovden of venous thrombosis with thrombocytopenia could be observed. e62 According to the recommendations of the American Society of Hematology, for a definitive diagnosis of VITT, all the following 5 criteria must be met: (1) COVID-19 vaccination 4–42 days before the onset of symptoms; (2) any venous or arterial thrombosis (often cerebral or abdominal); (3) thrombocytopenia (platelet count <150 × 109/L); (4) positive PF4 ″HIT” ELISA (heparin-induced thrombocytopenia); (5) markedly elevated D-dimers (>4 times upper limit of normal). e63 This must again be contrasted by the markedly increased risk of COVID-19–associated arterial and venous thrombosis, which is increased up to 1 year after infection. e64

Furthermore, an increased risk of postvaccinal Guillain-Barré syndrome has been reported in association with (nonreplicating) vector vaccines, in up to 1 in 10,000 vaccinated individuals, but not concerning mRNA vaccines. e65-e67 In a study by Bishara et al., the risk of Guillain-Barre-Syndrome (GBS) clearly increased after SARS-CoV-2 infection (odds ratio 6.3) and, by contrast, reduced after vaccination with the mRNA-based vaccine Comirnaty (odds ratio 0.41). e68 Similar observations had been reported earlier. e69 Moreover, the severity of the SARS-CoV-2 infections seems to heighten the risk of GBS. e70

In addition, the following other adverse events (AEs) have been reported in very small case numbers after SARS-CoV-2 vaccination: angioedema, capillary leak syndrome, extensive swelling of the vaccinated arm, facial swelling in individuals with a history of dermal filler injections, erythema multiforme, cutaneous small vessel vasculitis, transverse myelitis, paresthesia and hypesthesia, and immune thrombocytopenia. e71

Vaccine Hesitancy: Fears and Facts

Vaccination rates differ between countries. 10 This is partly due to the high cost of vaccines and partly to vaccination skepticism, a phenomenon that has become increasingly evident in light of the recent COVID-19 pandemic. 16 ,e72-e74

Regarding PwMS, especially in light of the new immunogenic vector-based and mRNA-based SARS-CoV-2 vaccines, there may be concern that vaccination (1) possibly causes MS, (2) may trigger a relapse and thus lead to disease activation, (3) may not be effective, and/or (4) lead to infertility or other severe AEs.

Can SARS-CoV-2 Vaccination Possibly Cause MS?

In this context, case reports of relapses or first clinical manifestations of MS emerging in temporal relation to SARS-CoV-2 vaccination have been published. e75-e79 However, individual cases are not able to establish any clear causality and several available studies, including large Class I and II evidence studies, argue against an association between SARS-CoV-2 vaccination and the development of MS. e80-e82 There is even evidence of a decreased likelihood of being diagnosed with MS after vaccination. e83,e84

Can SARS-CoV-2 Vaccination Trigger a Relapse?

There is no evidence available that MS relapses are triggered by vaccination, including yellow fever vaccination. e80,e85 Furthermore, in recent studies, the incidence of MS relapses after SARS-CoV-2 vaccination was not higher than in a comparative period before SARS-CoV-2 vaccination. e86-e89 Moreover, SARS-CoV-2 infection may lead to worsening of MS symptoms (Uhthoff phenomenon), which is known from other infections and vaccines. e80,e90,e91 At least 2 studies have shown that neither the risk of relapse nor of disability progression is increased in PwMS after a COVID-19 infection. e92,e93 A recent retrospective study drawing on data from the North American MS registry used a controlled interrupted time series design, and, in 796 PwMS, did not find evidence for an association of COVID-19 with disease activity, disability, progression, nor cognitive performance over 18 monthse. e94 Furthermore, preferably, prospective studies with a respective primary end point are desirable to further investigate this issue. Finally, vaccination may indirectly reduce the risk of suffering from pseudorelapse/relapse by preventing infections.

Are SARS-CoV-2 Vaccines Effective?

The efficacy of SARS-CoV-2 vaccination in general (see Introduction) and specifically in PwMS (see MS and COVID-19: Susceptibility, Severity, and Impact of DMTs section) is well established. e95-e97 However, especially with anti-CD20 B-cell–depleting therapies or S1P-R modulators as DMT, the humoral immune response to SARS-CoV-2 can be dampened with preserved and partly even enhanced cellular immune responses concerning anti-CD20 B-cell–depleting agents. e97-e112

Can SARS-CoV-2 Vaccination Lead to Infertility or Other Severe AEs?

Recent evidence indicates that both men and women, especially pregnant women, have no fertility problems or a higher propensity for adverse pregnancy outcomes after vaccination and, in particular, the benefits of maternal antibodies transferred through the placenta outweigh any known or potential risks. e113-e117 Contrarily, COVID-19 may be associated with a (temporary) decline in fertility (for infection within 60 days, the fecundability rate was 0.82). e118,e119

Other AEs are rare, such as myocarditis/pericarditis, VITT, or GBS (see SARS-CoV-2 Variants section). Moreover, AEs such as myocarditis or thrombosis occur more frequently after COVID-19 than after vaccination against SARS-CoV-2. e59,e64,e120,e121 This must always be considered in the risk-benefit assessment (vaccination-associated rare AEs vs probability of natural infection with potential ICU admission/fatality and AEs).

Finally, potential long-term side effects of the new gene-based vaccines cannot be ruled out, which is why phase IV postmarketing trials (actually 11 SARS-CoV-2 vaccines are in phase IV studies), as well as institutions such as the Vaccine Adverse Event Reporting System and the PRAC, are essential. e122 At least for mRNA-based vaccines, delayed AEs seem very unlikely, considering that mRNA remains relatively local (e.g., muscle cells) and is rapidly degraded. e123

MS and COVID-19: Susceptibility, Severity, and Impact of DMTs

Large observational studies have uniformly shown that PwMS do not seem to have a generally heightened risk of contracting SARS-CoV-2 or suffering a more severe disease course, although controversial evidence has been put forth. e124 As mentioned before, a recent study demonstrated that COVID-19 infection was not associated with changes in disease severity, disability, and progression, nor did it change disease trajectories over 18 months. e94 Risk factors associated with poor outcome are age, comorbidities, obesity, greater disability, and previous high-dose methylprednisolone treatment. e92,e93,e125-e131 A case-control study from the Italian MS registry using 3 different statistical models found female sex, comorbidities, younger age, escalation treatment, and exposure to natalizumab (NAT) as the last DMT to prognosticate a worse outcome. e132 In several other studies, no elevated risk of infection or a more severe disease course was found, particularly regarding various agents of all DMT classes, except B-cell–depleting DMTs. e133-e136 B-cell–depleting DMTs have in a number of studies, including a pooled analysis from the French and Italian cohort with 254 PwMS on rituximab or ocrelizumab, uniformly been shown to convey an elevated risk of severe COVID-19. e137-e140 Possible influencing factors include the interval since the last infusion regarding an emerging B-cell repopulation and thus a better humoral immune response as well as the duration of therapy and the associated risk of hypogammaglobulinemia. e141 Analysis of the same data sets also confirmed the possible beneficial effect of β-interferons as DMT regarding COVID-19, which is confirmed by other studies. e142 In another large international study of 657 suspected and 1,683 confirmed SARS-CoV-2 infections in PwMS, a clear association of rituximab and ocrelizumab with increased risk of hospitalization and ICU admission was demonstrated. e143 On the contrary, potential salutary effects of further DMTs (e.g., B-cell–depleting agents) on the overshooting immune response (e.g., cytokine storm) have been suggested. e137,e144-e146

SARS-CoV-2 Vaccination Immune Response, MS, and DMTs

The differences in immune responses after natural infection vs vaccination are not yet fully understood. In general, both natural infection and vaccination have been shown to induce protective humoral (spike protein–specific and nucleocapsid-specific IgG antibodies) and cellular (specific CD4 and CD8 T cells as well as memory B cells) immune responses. According to current data, immunity lasts up to 5–12 months and is influenced by factors such as age, the severity of the disease in the case of a natural infection, and underlying diseases and immunosuppressive therapies. 35 ,e147-e156 In a further study, individuals receiving the mRNA vaccine booster (Comirnaty or Spikevax) exhibited increased virus-neutralizing activity in plasma. However, in the group of convalescent individuals followed by the mRNA vaccine booster, a greater neutralizing breadth of antibodies was demonstrated to evolve over the comparative period of 5 months, especially regarding VOCs, signaling the superiority of hybrid immunity. Dejnirattisai et al. studied vaccinees who had received 2 doses of Comirnaty or Vaxzevria and observed a reduced ability of serum samples to neutralize the Omicron variant. This was ameliorated after a booster vaccination. e24 Similar findings were obtained by Garcia-Beltran et al. e157 Another research group detected strong humoral and cellular immune responses to the Omicron variant in individuals, who received a heterologous mRNA vaccine booster after administration of 2 doses of a vector vaccine. e39 Collective evidence indicates that the strongest immune response may be achieved in people with heterologous COVID-19 booster vaccinations and with hybrid immunity, in particular in the setting of natural infection and consecutive booster vaccination. e158-e163 In addition, several reports demonstrated that SARS-CoV-2 IgG titers are highly predictive of protection against symptomatic SARS-CoV-2 infection. However, a 7% monthly decrease in titer occurs and is likely responsible for the decline in vaccine protection. 32-36 ,e164,e165 Another published study showed strong cross-reactivity for Omicron after third vaccine dose in older residents, but decrease in the antibody titer of 21%–78% within 100 days after vaccination and breakthrough infection rate of 27%. e166 However, further evidence suggests that 87% of those vaccinated had a spike protein–specific memory T-cell response, and as mentioned before, T-cell responses in breakthrough infections after previous vaccination seem to be very fast and effective. e44,e167,e168

The investigations cited above have not examined the immune response in patients with autoimmune diseases such as MS. Most of the evidence regarding postvaccinal SARS-CoV-2 immune responses in PwMS under DMTs refers to the 2 mRNA vaccines (Comirnaty and Spikevax), and actually, their adapted versions ( Table 1 ) are recommended for vaccination by the Food and Drug Administration (FDA) and EMA. 7 ,e169 An important study by Sormani et al. demonstrated the following findings in PwMS after SARS-CoV-2 mRNA vaccination e99 :

Spikevax generates an antibody titer 3.25-fold higher than induced by Comirnaty. e170

A reduced humoral immune response was shown in patients on anti-CD20 B-cell–depleting therapies. SARS-CoV2 antibody titers increased on average after 143 days (4.6 months).

Similarly, for the S1P-R modulator fingolimod (FING), a diminished humoral immune response was observed.

For all other DMTs, especially cladribine (CLAD) (n = 25) and alemtuzumab (ALEM) (n = 15), an appropriate postvaccinal humoral immune response was detected, although the small sample sizes provide only limited evidence.

The dampened humoral immune response after SARS-CoV-2 vaccination with an mRNA vaccine for PwMS on anti-CD20 B-cell–depleting therapy and the increase in immune response with the time interval from the last infusion were confirmed in several studies and most likely reflect repopulation of B cells. e101,e105,e171-e183

Based on these observations, it has been suggested to perform vaccination at least 4 months after the last infusion of the depleting monoclonal antibody, or even better based on blood B-cell counts. e98,e104,e106,e107,e184-e186 In addition, it is noteworthy that those PwMS with reduced antibody formation and memory B cells were shown to launch an intact antigen-specific CD4 and CD8 T-cell response and even enhanced induction of CD8 T cells, with preserved priming of type 1 helper T cells. e100,e108,e172,e187-e190 However, reduced cellular immune responses were also observed in a different work. e191 Following on from this, a longitudinal study with deep immunoprofiling over a period of 12 months in CD20 B-cell–depleted patients (4 patients with MS, 1 patient with lupus and Sjögren syndrome) showed that CD20-positive B cells are necessary to generate a spike receptor-binding domain (RBD) titer that reflects the neutralizing antibody fraction well. e192 At the same time, this study also showed that a sustained T-cell response occurs even in the absence of seroconversion. In another longitudinal analysis of 42 PwMS, the frequency of SARS-CoV-2–positive B cells 1 month after the second vaccine dose was shown to correlate significantly with a higher antibody response to the second and third vaccine doses and antibody levels after the second vaccine dose may predict an efficient immune response to subsequent vaccine doses during ongoing anti-CD20 B-cell–depleting therapy. e193 Furthermore, a study of 60 patients on rituximab with underlying autoimmune disease (6 PwMS), who did not seroconvert after primary immunization with an mRNA vaccine, mounted a humoral immune response in 27% of cases after boosting homogeneously with the same mRNA vaccine or heterogeneously with the vector-based vaccine Vaxzevria. This clearly depended on B-cell repopulation after the last infusion that occurred within, on average, 6–7 months. After the vector-based booster, they generated a T-cell immune response in 100% of the cases and after the mRNA-based booster, in 81% of the cases. e101,e194 This strongly argues for third booster vaccination, even in nonseroconverted patients on B-cell–depleting therapy after full immunization.

In addition, a study by Räuber et al. showed that with each additional booster vaccination, the number of PwMS under anti-CD20 B-cell–depleting therapy with positive IgG antibody detection (seroconversion) increases. More specifically, after the second vaccination, 30.4% were positive; after the third, 56.5%; and after the fourth, 90%. In this context, it was demonstrated that one-third of PwMS who were seronegative after the second vaccination seroconverted after the third vaccination. e195 Of interest, in a study with 17 patients on ocrelizumab and with second vaccination with the protein subunit vaccine Nuvaxovid after lack of immunity due to previous mRNA/viral vector vaccination, 23.5% generated an adequate humoral immune response (predefined cutoff of 200 binding antibody units (BAU)/mL) and 53% generated a positive spike protein–specific T-cell response. e196 Moreover, a study investigated the immune response under different DMTs after infection with SARS-CoV-2 and found a persistent humoral and cellular immune response for up to 13 months, although anti-CD20–depleted PwMS showed a weakened humoral immune response with preserved cellular immunity, even in the absence of spike protein–specific antibodies. e175 How effectively T-cell immunity alone protects against COVID-19 and its severity in PwMS is still unclear, given the currently limited available data, and urgently requires further investigation, especially considering that PwMS on anti-CD20 B-cell depletion may have an increased risk of severe COVID-19 infection. e137,e197 Of note, preliminary evidence suggests that PwMS under ocrelizumab and with insufficient humoral immunity but preserved T-cell immunity are not at increased risk of COVID-19 or at least of severe courses. e195,e198,e199

Regarding the S1P-R modulators, Achiron et al. from Israel noted a distinctly weakened humoral immune response in FING-treated patients. However, the baseline lymphocyte count was very low and vaccination was exclusively performed using mRNA-based vaccines. e105,e106 In addition, regarding the cellular immune response to FING (n = 28), a B-cell response was detected in only 3.5% and a T-cell response in none of the patients. e105

These findings of reduced humoral and cellular immunity are confirmed by several studies, even after third vaccination, in particular also in a multicenter study with 63 PwMS on S1P-R modulators. e105-e107,e176-e182,e185,e186,e190,e200-e202 In addition, in this multicenter study, no correlation of IgG levels with absolute lymphocyte count at the time point of vaccination could be found, although contradictory data exist. e180,e203 Remarkably, a study of 8 patients on FING showed that 50% developed a relevant antibody titer after the third vaccination (cutoff 100 AU/mL), and another study, including 9 FING-treated patients, showed 100% seroconversion after the third vaccination, albeit with clearly reduced titers compared with healthy controls. e177,e204 It has also been shown that vaccination with a vector-based vaccine may be more likely lead to significant immune protection than with a mRNA-based vaccine, especially with the use of S1P-R modulators. This observation raises the possibility that the immune responses elicited may depend on the mode of action of the SARS-CoV-2 vaccine. e203,e205,e206 One mechanistic hypothesis holds that interaction of lipophilic S1P-R modulators with mRNA nanoparticles may affect the integrity and the immune response of mRNA vaccines. e205

On top of that, a review article indicates that the pharmacokinetics and the lack of binding to the S1P4 receptor of the newer S1P-R modulators (siponimod, ozanimod, ponesimod) and the resulting lower influence on natual killer cells and subsequently dendritic cells could lead to better humoral immunity than with the primary agent FING. e207 Moreover, in a study with 47 patients on S1P-R modulator therapy and with second vaccination with the protein subunit vaccine Nuvaxovid after lack of immunity due to previous mRNA/viral vector vaccination, 59% generated an adequate humoral immune response (predefined cutoff of 200 BAU/mL) after vaccination, although cellular immunity was still lacking. e196,e199 It has been hypothesized that this might be due to different antigens with potentially different immunogenicity. e196

Particularly, for CLAD and ALEM, an appropriate humoral immune response was demonstrated in most of the available studies, although with at least in part low case numbers. e99,e105-e107,e179-e182,e185,e186,e202 In 1 study, humoral immune response was even increased in CLAD-treated PwMS compared with HCs while a few studies showed partly reduced humoral immune response. e177,e178,e181,e182,e200 Notably, in the study by Achiron et al., patients on ALEM treatment (n = 22) showed a slightly decreased responder rate (86.4%). e105 A further study by Achiron on 12 PwMS under ALEM showed an effective humoral and cellular immune response compared with untreated PwMS after second vaccination, which was further increased by a third shot. e208

In the study by Sormani et al. with therapy using the DMTs glatiramer acetate (GLAT) (n = 38), β-interferons (n = 79), dimethyl fumarate (DMF) (n = 114), teriflunomide (TERI) (n = 48), NAT (n = 100), and others (n = 10), adequate humoral immune responses after vaccination with an mRNA-based vaccine were recorded e99 . These findings are again confirmed by several independent studies. e104-e107,e177,e179-e182,e185,e186,e189,e200-e202,e208 For ß-interferons, an even heightened humoral immune response compared with HCs could be observed, which is in line with evidence of a reduced risk of COVID-19 in ß-interferon–treated PwMS. e137,e142,e178

Limited data from the study by Achiron et al. indicate that spike protein–specific IgG longevity is impaired on therapy with FING, ocrelizumab, and rituximab, but not on treatment with ALEM, CLAD, DMF, NAT, or TERI, when compared with HCs and untreated PwMS. e105 A second study demonstrated a reduced spike protein–specific longevity under DMT with DMF, interferon β-1a, and GLAT. By contrast, even higher antibody titer persistence was observed in this study under DMT with TERI and NAT than in HCs. e200

Finally, COVID-19 vaccines (mRNA and nonreplicating vector-based vaccines) currently approved by the FDA and EMA are equivalent, regarding applicability in immunosuppressed patients, to nonlive vaccines in clinical practice and, therefore, can be administered at any time and with any available DMTs. 8 ,e82 In patients receiving anti-CD20 B-cell–depleting therapies, CLAD, or ALEM, postponing the next dose can be useful in achieving a protective humoral immune response.

Therefore, a minimum interval of 4 months after the last infusion of an anti-CD20 lymphocyte-depleting therapy is recommended for vaccination together with B-cell monitoring. By contrast, interferons (INTFs) might even have a positive influence on the humoral immune response. e178

Table 2 summarizes humoral immune response to SARS-CoV-2 vaccines (mainly mRNA vaccines) and SARS-CoV-2 infection in PwMS regarding respective DMTs. The studies listed in Table 2 were selected based on case numbers and regarding the number of different DMTs investigated. Hence, not all published studies are listed here.

Table 2 Humoral Immune Response on a DMT After SARS-CoV-2 Vaccination and SARS-CoV-2 Infection Humoral immune response DMT Vaccination Infection Sormani et al. e99 Achiron et al. e105,e106,e208 König et al. e185 Pitzalis et al. e181 Milo et al. e180 Bsteh et al. e203 Tallantyre et al. e202 Tortorella et al. e182 Disanto et al. e107,e186 Capuano et al. e176 Zabalza et al. e175 Bsteh et al. e206 Habek et al. e209 GLAT √ — (√) √ √ √ (√) — — — (√) (√) — INTFs √ — (√) √ √ √ (√) √ — — (√) (√) — DMF √ √ √ √ √ √ √ — — — (√) (√) — TERI √ √ √ ∼ √ (√) (√) — √ — (√) (√) — NAT √ √ √ ∼ √ √ √ — — — (√) (√) (√) CLAD √ √ √ — √ ∼ (√) ∼ (√) — (√) (∼) (∼) ALEM (√) ∼ √ (√) (√) (∼) √ — — — (√) (↘) (√) FING ↘ ↘ ↘ ↘ ↘ ↘ ↘ ↘ (↘) ↘ (∼) (∼) (↘) Anti-CD20 ↘ ↘ ↘ ↘ ↘ ↘ ↘ ↘ ↘ ↘ ↘ ↘ ↘ Abbreviations:ALEM = alemtuzumab; anti-CD20 = CD20 B-cell–depleting therapies (rituximab, ocrelizumab, ofatumumab); CLAD = cladribine; DMT = dimethyl fumarate; FING = fingolimod; GLAT = glatiramer acetate; INTFs = interferons; NAT = natalizumab; TERI = teriflunomide. √ = appropriate humoral immune response, (√) = appropriate humoral immune response shown but small sample size (n < 20). ↘ = reduced humoral immune response, (↘) = reduced humoral immune response shown but small sample size (n < 20). ∼ = most likely minorly reduced humoral immune response, (∼) = most likely minorly reduced humoral immune response shown but small sample size (n < 20).

Humoral Immune Response on a DMT After SARS-CoV-2 Vaccination and SARS-CoV-2 Infection

Abbreviations:ALEM = alemtuzumab; anti-CD20 = CD20 B-cell–depleting therapies (rituximab, ocrelizumab, ofatumumab); CLAD = cladribine; DMT = dimethyl fumarate; FING = fingolimod; GLAT = glatiramer acetate; INTFs = interferons; NAT = natalizumab; TERI = teriflunomide.

√ = appropriate humoral immune response, (√) = appropriate humoral immune response shown but small sample size (n < 20).

↘ = reduced humoral immune response, (↘) = reduced humoral immune response shown but small sample size (n < 20).

∼ = most likely minorly reduced humoral immune response, (∼) = most likely minorly reduced humoral immune response shown but small sample size (n < 20).

Recommendations

In general, the recommendations given by a number of MS societies internationally regarding the specific situation of the pandemic and SARS-CoV-2 vaccines in PwMS are in agreement e210-e213 :

COVID-19 does not pose an increased risk of MS per se. PwMS should follow the general WHO recommendations for prevention of COVID-19, including COVID-19 vaccination.

To date, there is no clear evidence that SARS-CoV-2 vaccines cause or trigger a relapse or initial manifestation of MS.

Current evidence indicates that DMTs are not associated with an increased risk of COVID-19 or a more severe disease course except for anti-CD20 B-cell–depleting therapies. Of note, INTFs may have a beneficial effect on the course of COVID-19.

In general, PwMS should continue their DMT. While on an anti-CD20 B-cell–depleting DMT or a S1P-R modulator, a weakened humoral immune response may occur, although a sustained and partly even enhanced cellular immunity can be expected, at least regarding anti-CD20 B-cell–depleting DMT.

Gene-based COVID-19 vaccines (mRNA and nonreplicating vector-based vaccines) are assumed to be equivalent, regarding applicability in immunosuppressed patients, to nonlive vaccines in clinical practice and, therefore, can be safely administered at any time and with any available DMTs in PwMS. However, depending on the individual situation, delaying the next dose of cyclic-administered DMTs (anti-CD20 B-cell–depleting DMTs, ALEM, and CLAD) may be considered because this may generate better protective humoral immune responses ( Table 3 ). Monitoring B-cell repopulation in this context may be useful.

In general, recommendations from national/local authorities should always be considered regarding further SARS-CoV-2 vaccination and factors such as age, progressive disease form, degree of disability, and pregnancy; risk factors such as cardiovascular diseases; and immunosuppressive DMTs should be taken into account. For instance, according to the FDA and CDC, every individual 6 months or older, who did not receive a COVID-19 vaccine in the previous 2 months, should receive a booster vaccination (age 6 months to 4 years may need more doses) with the currently available adapted ( Table 1 ) mRNA vaccines to generate a better protection in the season 2024/2025, considering the current VOC situation. e214,e215

COVID-19 vaccines are highly effective and exhibit a good safety profile overall. Nonetheless, both treating neurologists and PwMS should remain vigilant for rare AEs such as myocarditis, pericarditis, VITT, or GBS.

Table 3 SARS-CoV-2 mRNA Vaccines, Their Humoral Immune Response, and Consecutive Recommendations for the Time Point of Vaccination in PwMS Under Corresponding DMT mRNA vaccines a GLAT INTFs DMF TERI CLAD FING NAT ALEM anti-CD20 Ab-Re
√

√

√

√

√

↘

√

√

↘
ToV Anytime Anytime Anytime Anytime Anytime # Anytime Anytime Anytime # ≥ 4 mo Abbbreviations: Ab-Re = antibody response, ToV = time of vaccination; ALEM = alemtuzumab; anti-CD20 = CD20-B cell–depleting therapies (rituximab, ocrelizumab, ofatumumab); CLAD = cladribine; DMT = dimethyl fumarate; FING = fingolimod; GLAT = glatiramer acetate; INTFs = interferons; NAT = natalizumab; TERI = teriflunomide. √ = appropriate humoral immune response. (√) = appropriate humoral immune response but small sample size. ↘ = reduced humoral immune response. # = setting time of vaccination ≥ 3–6 mo after the last administration may be reasonable to optimize humoral immune response. a eReferences e82, e98, e99, e104-e107, e176-e182, e185, e186, e189, e190, e200-e202, e208, e213.

SARS-CoV-2 mRNA Vaccines, Their Humoral Immune Response, and Consecutive Recommendations for the Time Point of Vaccination in PwMS Under Corresponding DMT

Abbbreviations: Ab-Re = antibody response, ToV = time of vaccination; ALEM = alemtuzumab; anti-CD20 = CD20-B cell–depleting therapies (rituximab, ocrelizumab, ofatumumab); CLAD = cladribine; DMT = dimethyl fumarate; FING = fingolimod; GLAT = glatiramer acetate; INTFs = interferons; NAT = natalizumab; TERI = teriflunomide.

√ = appropriate humoral immune response.

(√) = appropriate humoral immune response but small sample size.

↘ = reduced humoral immune response.

# = setting time of vaccination ≥ 3–6 mo after the last administration may be reasonable to optimize humoral immune response.

eReferences e82, e98, e99, e104-e107, e176-e182, e185, e186, e189, e190, e200-e202, e208, e213.

Conclusion

Overall, vaccination against COVID-19, especially for PwMS, represents a very important step in combating this ongoing pandemic, besides other actions. e216 COVID-19 vaccination should be administered following national recommendations and especially also in PwMS, factors such as age, progressive disease form, degree of disability, and pregnancy; risk factors such as cardiovascular diseases; and immunosuppressive DMTs should be taken into account. 7 ,e169,e217,e218 Comparatively, these factors are also very important for those who are vaccine skeptical because the risk of potential COVID-19 disease may be significantly increased in at-risk individuals. According to the FDA and CDC, for the season 2024/2025, a booster vaccination with one of the adapted mRNA vaccines ( Table 1 ) is generally recommended at least 2 months after the previous vaccination to be better protected against SARS-CoV-2 infection, especially under the aspect of current VOCs. e214,e215 PwMS should, in general, continue DMTs in the context of the COVID-19 pandemic and should attend regular follow-up visits with the neurologist responsible for their care. e210-e213 Regarding anti-CD20 B-cell–depleting DMTs, ALEM, and CLAD, deferring the next dose may be reasonable to obtain a sufficient humoral immune response. e98,e104,e106,e107,e210-e213 While evidence is limited, patients receiving an S1P-R modulator may benefit from the preferential use of a vector-based vaccine or an inactivated protein-based vaccine—the latter also concerns PwMS with anti-CD20 B-cell–depleting DMT. e196,e203,e205,e206 According to currently available evidence, all other DMTs mainly do not affect humoral immune responses to FDA-approved and EMA-approved mRNA-based vaccines ( Table 2 ).

Acknowledgment

The authors thank Dr. AG Willison for critical review and Michael Schwarz, MSc, for support in graphic creation.

Glossary

adverse event

alemtuzumab

dimethyl fumarate

disease-modifying therapy

European Medicines Agency

fingolimod

glatiramer acetate

intensive care unit

interferon

multiple sclerosis

natalizumab

Pharmacovigilance Risk Assessment Committee

people with MS

teriflunomide

vaccine-induced thrombotic thrombocytopenia

variant of concern

variant of interest

World Health Organization

Author Contributions

T. Monschein: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. T. Zrzavy: analysis or interpretation of data. P.S. Rommer: analysis or interpretation of data. S.G. Meuth: analysis or interpretation of data. A. Chan: analysis or interpretation of data. T. Berger: analysis or interpretation of data. H.-P. Hartung: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data.

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/NN for full disclosures.

References