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Vaccination of multiple sclerosis patients during the COVID-19 era: Novel insights into vaccine safety and immunogenicity

Published:September 09, 2022DOI:https://doi.org/10.1016/j.msard.2022.104172

      Highlights

      • Young adults with multiple sclerosis may not be at higher risk for COVID-19.
      • Anti-CD20 therapies are associated with more severe COVID-19 infection.
      • COVID-19 vaccines do not appear to promote multiple sclerosis relapse or development.
      • Fingolimod and anti-CD20 treatments can reduce vaccine efficacy.
      • Except live vaccines, most vaccinations are safe and effective in this population.

      Abstract

      Multiple sclerosis (MS) is an incurable autoimmune disease known to cause widespread demyelinating lesions in the central nervous system (CNS) and a host of debilitating symptoms in patients. The development of MS is believed to be driven by the breakdown of the blood brain barrier, subsequent infiltration by CD4+ and CD8+ T cells, and widespread CNS inflammation and demyelination. Disease modifying therapies (DMTs) profoundly disrupt these processes and therefore compose an essential component of disease management. However, the effects of these therapeutic agents on vaccine safety and immunogenicity in individuals with MS are not yet fully understood. As such, the primary objective of this review article was to summarize the findings of recently conducted studies on vaccine safety and immunogenicity in MS patients treated with DMTs, particularly in the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Discussed in this review are vaccinations against influenza, yellow fever, human papillomavirus, measles, mumps, rubella, Streptococcus pneumoniae, hepatitis B, and COVID-19. This article additionally reviews our current understanding of COVID-19 severity and incidence in this patient population, the risks and benefits of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and vaccination guidelines set forth by MS societies and organizations.

      Keywords

      Abbreviations:

      MS (multiple sclerosis), CNS (central nervous system), DMTs (disease modifying therapies), COVID-19 (coronavirus disease 2019), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)

      1. Introduction

      Multiple sclerosis (MS) is a chronic autoimmune disease known to cause widespread demyelination and functional disruption of the central nervous system. Although MS is not a hereditary disease, several key genetic and environmental factors that predispose individuals to MS have been identified. A Canadian study confirmed a pattern of increased familial risk for this autoimmune disease (
      • Sadovnick A.D.
      • Ebers G.C.
      • Dyment D.A.
      • Risch N.J.
      Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group.
      ). According to their findings, the risk for developing MS is 300-fold greater in monozygotic twins when one sibling is affected and at least 20-fold greater in individuals with first-degree family members suffering from MS (
      • Sadovnick A.D.
      • Ebers G.C.
      • Dyment D.A.
      • Risch N.J.
      Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group.
      ). Of note, the disease is closely linked to certain major histocompatibility complexes including HLA-DRB1. Various environmental factors like vitamin D deficiency, teenage obesity, exposure to tobacco smoke, and infections by Epstein-Barr virus and Human Herpes Virus 6 have also been linked to a higher risk of MS development (
      • Kamm C.P.
      • Uitdehaag B.M.
      • Polman C.H.
      Multiple sclerosis: current knowledge and future outlook.
      ;
      • Guan Y.
      • Jakimovski D.
      • Ramanathan M.
      • Weinstock-Guttman B.
      • Zivadinov R.
      The role of Epstein-Barr virus in multiple sclerosis: from molecular pathophysiology to in vivo imaging.
      ;
      • Olsson T.
      • Barcellos L.F.
      • Alfredsson L.
      Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis.
      ).
      Though the mechanisms by which multiple sclerosis arises are still unclear, the disruption of the blood brain barrier (BBB) is thought to be one of the earliest events that initiate the disease process. With the breakdown of the BBB, various immune cells including CD4+ and CD8+ T lymphocytes are then able to gain access to the central nervous system (CNS) (
      • Al-Badri G.
      • Castorina A.
      Insights into the role of neuroinflammation in the pathogenesis of multiple sclerosis.
      ). T lymphocytes are considered the main effector cells primarily responsible for mediating the auto-reactive immune responses characteristic of this condition. Myelin is perceived as foreign by these immune cells, and as a direct consequence, is damaged by the resulting cytokines and reactive oxygen species released by activated lymphocytes (
      • Al-Badri G.
      • Castorina A.
      Insights into the role of neuroinflammation in the pathogenesis of multiple sclerosis.
      ;
      • Dendrou C.A .FL.
      • Friese M.A
      Immunopathology of multiple sclerosis. Review.
      ;
      • Ghasemi N.
      • Razavi S.
      • Nikzad E.
      Multiple Sclerosis: pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy.
      ). Among other functions, CD4+ T cells are also known to recruit other immune cells such as macrophages and B cells during this process, while CD8+ T cells are believed to attack the MHC class I-expressing oligodendrocytes and neurons (
      • Hemmer B.
      • Nessler S.
      • Zhou D.
      • Kieseier B.
      • Hartung H.P.
      Immunopathogenesis and immunotherapy of multiple sclerosis.
      ). What ultimately follows is widespread CNS inflammation, axonal loss and damage, and a cyclical pattern of demyelination and remyelination, all of which contribute to the plaque formation and clinical manifestations of MS (
      • Dendrou C.A .FL.
      • Friese M.A
      Immunopathology of multiple sclerosis. Review.
      ;
      • Ghasemi N.
      • Razavi S.
      • Nikzad E.
      Multiple Sclerosis: pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy.
      ;
      • Dargahi N.
      • Katsara M.
      • Tselios T.
      • et al.
      Multiple Sclerosis: immunopathology and Treatment Update.
      ).
      Despite its incurable nature, multiple sclerosis can be treated and managed effectively with corticosteroids and disease modifying therapies (DMTs), an immunomodulatory class of drugs that include interferons and monoclonal antibody biologics like natalizumab (
      • Dargahi N.
      • Katsara M.
      • Tselios T.
      • et al.
      Multiple Sclerosis: immunopathology and Treatment Update.
      ). DMTs not only improve the quality of life for MS patients through symptomatic relief but also reduce the frequency, severity, and duration of relapses (
      • Cree B.A.C.
      Multiple sclerosis.
      ). Inherent to these drugs, however, is their ability to suppress the elements of the immune system chiefly responsible for the symptoms and complications associated with this debilitating disease. Thus, infections are a common concern for patients suffering from MS and unfortunately, the primary cause of death in this population (
      • Smestad C.
      • Sandvik L.
      • Celius E.G.
      Excess mortality and cause of death in a cohort of Norwegian multiple sclerosis patients.
      ). In fact, MS patients are more likely to contract serious infections, experience more severe symptoms, and succumb to their infections relative to the general population (
      • Montgomery S.
      • Hillert J.
      • Bahmanyar S.
      Hospital admission due to infections in multiple sclerosis patients.
      ;
      • Celius E.G.
      Infections in patients with multiple sclerosis: implications for disease-modifying therapy.
      ;
      • Nelson R.E.
      • Xie Y.
      • DuVall S.L.
      • et al.
      Multiple Sclerosis and Risk of Infection-Related Hospitalization and Death in US Veterans.
      ). As such, vaccination of this population is crucial, both as a means to prevent infections preemptively and to reduce the severity of disease should they arise.
      The emergence of the deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, aptly named coronavirus disease 2019 (COVID-19), has only highlighted the need for vaccination of individuals living with MS. Considering a greater proportion of MS patients possess established risk-factors for COVID-19 infection including heart disease and hypertension, experts have strongly encouraged MS patients to undergo COVID-19 vaccination (
      • Palladino R.
      • Marrie R.A.
      • Majeed A.
      • Chataway J.
      Evaluating the Risk of Macrovascular Events and Mortality Among People With Multiple Sclerosis in England.
      ). Three vaccines against SARS-CoV-2 are currently available in the United States: the Moderna (mRNA-1273), Pfizer/BioNTech (BNT162b2) and Johnson & Johnson (JNJ 78436735) vaccines. The Moderna and Pfizer/BioNTech vaccines are FDA-approved messenger RNA (mRNA) vaccines while the Johnson & Johnson vaccine is based on a non-replicating adenoviral vector (

      FDA Approves First COVID-19 Vaccine. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19-vaccine. Accessed March 15, 2022.

      ;
      Coronavirus (COVID-19) update
      FDA Takes Key Action By Approving Second COVID-19 Vaccine.
      ). All three vaccines deliver RNA or DNA encoding for the spike protein of SARS-CoV-2 into host cells, thereby inducing a humoral immune response that ultimately affords patients vital protection from future infection.
      The safety of vaccinations in the MS population has been investigated comprehensively in recent years. However, the literature regarding the immunogenicity of various vaccinations in this population, especially with the advent of new vaccine advancements such as those utilized in the COVID-19 vaccines, remains scant. The goal of this review is to summarize currently available data and ongoing research on the safety and immunogenicity of various vaccines in MS patients, particularly in the context of DMTs and the ongoing COVID-19 pandemic.

      2. COVID-19 and multiple sclerosis

      Most concerning for millions of MS patients is the ongoing COVID-19 pandemic. Concerns have been raised not only about the increased risk of contracting COVID-19 but also the potentially greater severity of disease and higher rate of mortality in infected MS patients. Preliminary studies conducted in France, Spain, and Iran found that MS patients with COVID-19 are at greater risk for hospitalization and adverse health outcomes (
      • Louapre C.
      • Collongues N.
      • Stankoff B.
      • et al.
      Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis.
      ;
      • F Castillo Álvarez
      • MÁ López Pérez
      • Marzo Sola M.E
      Risk of SARS-CoV-2 infection and clinical outcomes in multiple sclerosis patients in La Rioja (Spain): riesgo de infección por SARS-CoV-2 y resultados clínicos en pacientes con esclerosis múltiple en la Rioja (España).
      ;
      • Sahraian M.A.
      • Azimi A.
      • Navardi S.
      • Ala S.
      • Naser Moghadasi A
      Evaluation of the rate of COVID-19 infection, hospitalization and death among Iranian patients with multiple sclerosis.
      ).
      However, these findings demonstrating increased risk have not been met with consensus confirmation. An earlier Chinese study and a recent cohort study involving MS patients from the United Kingdom, United States, and Canada determined overall health outcomes and risk of severe COVID-19 infection to be comparable to that of the general population (
      • Fan M.
      • Qiu W.
      • Bu B.
      • et al.
      Risk of COVID-19 infection in MS and neuromyelitis optica spectrum disorders.
      ;
      • Salter A.
      • Fox R.J.
      • Newsome S.D.
      • et al.
      Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis.
      ). Most notably, a systematic review encompassing 87 studies and involving 4310 MS patients with COVID-19 infection determined that hospitalization and mortality rates in this population are within the published ranges of the general population (
      • Barzegar M.
      • Mirmosayyeb O.
      • Gajarzadeh M.
      • et al.
      COVID-19 Among Patients With Multiple Sclerosis: a Systematic Review.
      ). Though encouraging, these data should be interpreted with caution. Given that this study's participants were predominantly young and female, and therefore less likely to require hospitalization, studies conducted on more diverse patient groups will be needed to confirm these findings.
      Furthermore, there may be a subset of this MS patient population that is more at risk. Namely, individuals relying on DMTs for symptom management and relapse prevention are thought to be more susceptible to COVID-19 infection. Two Iranian studies observed that the use of B-cell depleting therapies, like rituximab and ocrelizumab, by MS patients can heighten their risk for developing COVID-19 (
      • Sahraian M.A.
      • Azimi A.
      • Navardi S.
      • Ala S.
      • Naser Moghadasi A
      Evaluation of the rate of COVID-19 infection, hospitalization and death among Iranian patients with multiple sclerosis.
      ;
      • Safavi F.
      • Nourbakhsh B.
      • Azimi A.R.
      B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran.
      ). Considering these therapeutic agents target and eliminate circulating B-cells and therefore blunt humoral immune responses to infections, the use of these monoclonal antibodies is expected to increase the susceptibility of MS patients to infections of any kind which was previously confirmed in a Swedish study (
      • Luna G.
      • Alping P.
      • Burman J.
      • et al.
      Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies.
      ).
      Along with a heightened susceptibility to COVID-19 infection, a higher risk of severe infection has also been noted in MS patients treated with anti-CD20 monoclonal antibodies. Specifically, a Swedish cohort study determined that MS patients on rituximab or ocrelizumab were 3 times more likely to require hospitalization relative to those treated by any other DMT (
      • Spelman T.
      • Forsberg L.
      • McKay K.
      • Glaser A.
      • Hillert J.
      Increased rate of hospitalisation for COVID-19 among rituximab-treated multiple sclerosis patients: a study of the Swedish multiple sclerosis registry.
      ). A 2021 study analyzing data collected from 2300 COVID-19-infected MS patients in 28 countries including Sweden came to a similar conclusion; rituximab use was associated with significantly higher hospitalization, intubation, and intensive care unit admission rates than treatment with any other DMT (
      • Simpson-Yap S.
      • De Brouwer E.
      • Kalincik T.
      • et al.
      Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis.
      ). Compared to those not receiving DMTs, MS patients on B-cell depleting therapy have also been documented to be at a 4-fold higher risk of severe COVID-19 and 4.5 times more likely to be hospitalized as determined by Italian and North American multicenter studies (
      • Salter A.
      • Fox R.J.
      • Newsome S.D.
      • et al.
      Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis.
      ;
      • Sormani M.P.
      • Inglese M.
      • Schiavetti I.
      • et al.
      Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
      ). Altogether, rituximab and ocrelizumab appear to not only heighten susceptibility to infection but confer risk for more severe COVID-19 in MS patients.
      In contrast, the use of interferons and glatiramer acetate by MS patients does not appear to be linked to higher COVID-19 incidence or greater disease severity according to recently published data (
      • Louapre C.
      • Collongues N.
      • Stankoff B.
      • et al.
      Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis.
      ;
      • Sahraian M.A.
      • Azimi A.
      • Navardi S.
      • Ala S.
      • Naser Moghadasi A
      Evaluation of the rate of COVID-19 infection, hospitalization and death among Iranian patients with multiple sclerosis.
      ;
      • Salter A.
      • Fox R.J.
      • Newsome S.D.
      • et al.
      Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis.
      ;
      • Chaudhry F.
      • Bulka H.
      • Rathnam A.S.
      • et al.
      COVID-19 in multiple sclerosis patients and risk factors for severe infection.
      ). In fact, two studies noted that rates of severe COVID-19 infection were higher in MS patients not receiving DMTs, suggesting that these therapeutics may impart some degree of protection to MS patients (
      • Louapre C.
      • Collongues N.
      • Stankoff B.
      • et al.
      Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis.
      ;
      • Chaudhry F.
      • Bulka H.
      • Rathnam A.S.
      • et al.
      COVID-19 in multiple sclerosis patients and risk factors for severe infection.
      ). These findings are largely consistent with early speculations that DMTs can mitigate the severity of the cytokine-storms characteristic of COVID-19 infections; a recent study even observed interferon-β treatment was associated with significantly shorter hospital stays, reduced mortality, and decreased likelihood of mechanical ventilation (
      • Berger J.R.
      • Brandstadter R.
      Bar-Or A. COVID-19 and MS disease-modifying therapies.
      ;
      • Sosa J.P.
      • Ferreira Caceres M.M.
      • Ross Comptis J.
      • et al.
      Effects of Interferon Beta in COVID-19 adult patients: systematic Review.
      ). As such, experts agree that continued interferon and glatiramer acetate use is likely safe in MS patients, but many still caution that certain high-efficacy DMTs, such as natalizumab and fingolimod, can impair MS patient immune responses to COVID-19 (
      • Berger J.R.
      • Brandstadter R.
      Bar-Or A. COVID-19 and MS disease-modifying therapies.
      ;
      • Kappos L.
      • Mehling M.
      • Arroyo R.
      • et al.
      Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis.
      ;
      • Giovannoni G.
      • Hawkes C.
      • Lechner-Scott J.
      • Levy M.
      • Waubant E.
      • Gold J.
      The COVID-19 pandemic and the use of MS disease-modifying therapies.
      ;
      • Korsukewitz C.
      • Reddel S.W.
      • Bar-Or A.
      • Wiendl H.
      Neurological immunotherapy in the era of COVID-19 - looking for consensus in the literature.
      ).

      3. COVID-19 vaccine

      Of current concern are also the adverse effects, relapse potential, and reduced immunogenicity of the newly developed COVID-19 vaccines in MS patients. Indeed, when assessing MS patients’ attitudes towards vaccination, many reported reluctance and even fear about the adverse effects and potential complications of COVID-19 vaccines, particularly in the context of DMTs (
      • Ehde D.M.
      • Roberts M.K.
      • Herring T.E.
      • Alschuler K.N.
      Willingness to obtain COVID-19 vaccination in adults with multiple sclerosis in the United States.
      ;
      • Serrazina F.
      • Sobral Pinho A.
      • Cabral G.
      • Salavisa M.
      • Correia A.S
      Willingness to be vaccinated against COVID-19: an exploratory online survey in a Portuguese cohort of multiple sclerosis patients.
      ). According to recently published data from two major studies, adverse effects associated with the Oxford-AstraZeneca and Pfizer/BioNTech vaccines appear to occur in MS patients at a frequency and severity similar to the general population (Table 1) (
      • FBS Mateen FJ
      • Schmidt H.
      • et al.
      COVID-19 Vaccination Reactogenicity in Persons With Multiple Sclerosis.
      ;
      • Achiron A.
      • Dolev M.
      • Menascu S.
      • et al.
      COVID-19 vaccination in patients with multiple sclerosis: what we have learnt by February 2021.
      ;
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.
      ). In these cohorts, both first and second doses of either vaccine led to transient reactions typical of healthy individuals, such as fatigue, headache, and fever (
      • FBS Mateen FJ
      • Schmidt H.
      • et al.
      COVID-19 Vaccination Reactogenicity in Persons With Multiple Sclerosis.
      ;
      • Achiron A.
      • Dolev M.
      • Menascu S.
      • et al.
      COVID-19 vaccination in patients with multiple sclerosis: what we have learnt by February 2021.
      ). Though noted in several case reports, disease relapse is also believed to be a rare occurrence in MS patients following vaccination (
      • Etemadifar M.
      • Sigari A.A.
      • Sedaghat N.
      • Salari M.
      • Nouri H.
      Acute relapse and poor immunization following COVID-19 vaccination in a rituximab-treated multiple sclerosis patient.
      ;
      • Fujimori J.
      • Miyazawa K.
      • Nakashima I.
      Initial clinical manifestation of multiple sclerosis after immunization with the Pfizer-BioNTech COVID-19 vaccine.
      ;
      • Havla J.
      • Schultz Y.
      • Zimmermann H.
      • Hohlfeld R.
      • Danek A.
      • Kümpfel T.
      First manifestation of multiple sclerosis after immunization with the Pfizer-BioNTech COVID-19 vaccine.
      ). An Israeli observational study independently confirmed these suspicions, demonstrating through its findings that relapse rates between vaccinated and unvaccinated MS patients are virtually indistinguishable (
      • Achiron A.
      • Dolev M.
      • Menascu S.
      • et al.
      COVID-19 vaccination in patients with multiple sclerosis: what we have learnt by February 2021.
      ).
      Table 1Landmark Studies Evaluating Safety and Immunogenicity of COVID-19 Vaccines in Individuals Living with MS.
      YearLocationStudy PopulationDMTVaccineNotable Findings
      2020United States, Argentina, Brazil, South Africa, Germany, and Turkey43,448 patients (21,720 with BNT162b2; 21,728 with placebo)N/ABNT162b2 or placeboTwo-dose regimen of the BNT162b2 vaccine is both safe and effective against COVID-19 (
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.
      )
      2021Israel555 MS patients (1st dose); 435 MS patients (2nd dose)Interferons, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab, fingolimod, ocrelizumab, alemtuzumab, cladribine, or rituximabBNT162b2No evidence of heightened relapse activity following vaccination (
      • Achiron A.
      • Dolev M.
      • Menascu S.
      • et al.
      COVID-19 vaccination in patients with multiple sclerosis: what we have learnt by February 2021.
      )
      2021United States719 MS patients (1st dose); 442 MS patients (2nd dose)B-cell depleting therapies, fumarates, S1P receptor modulators, glatiramer acetate, natalizumab, interferons, alemtuzumab, or cladribineBNT162b2, mRNA-1273, Ad26.COV2.S, or ChAdOx1 nCoV-1Vaccination side effects occur in patients with MS at a similar frequency and severity as the general population (
      • FBS Mateen FJ
      • Schmidt H.
      • et al.
      COVID-19 Vaccination Reactogenicity in Persons With Multiple Sclerosis.
      )
      2021Israel172 patients (125 MS patients; 47 healthy control patients)Cladribine, ocrelizumab, or fingolimodBNT162b2Most fingolimod-treated patients did not develop SARS-CoV-2 antibodies, unlike a vast majority of cladribine-treated patients (
      • Achiron A.
      • Mandel M.
      • Dreyer-Alster S.
      • et al.
      Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.
      ). Ocrelizumab treatment was also noted to impair humoral responses to vaccination (
      • Achiron A.
      • Mandel M.
      • Dreyer-Alster S.
      • et al.
      Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.
      ).
      2021United States and Denmark60 MS patientsOcrelizumabBNT162b2 or mRNA-1273Markedly reduced humoral responses to SARS-CoV-2 vaccines is evident with ocrelizumab treatment (
      • Apostolidis S.A.
      • Kakara M.
      • Painter M.M.
      • et al.
      Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.
      )
      2021Switzerland49 MS patientsOcrelizumab or rituximabBNT162b2 or mRNA-1273Of 16 patients treated with B-cell depleting therapy, only one developed humoral immunity to SARS-CoV-2 after 3rd vaccine dose (
      • Achtnichts L.
      • Jakopp B.
      • Oberle M.
      • et al.
      Humoral Immune Response after the Third SARS-CoV-2 mRNA Vaccination in CD20 Depleted People with Multiple Sclerosis.
      )
      2021Switzerland120 MS patientsB-cell depleting therapies, S1P receptor modulators, cladribine, or teriflunomideBNT162b2 or mRNA-1273While cladribine or teriflunomide treatment was not associated with reduced humoral responses to vaccination, B-cell depleting therapies and S1P receptor modulator treatment led to significantly impaired immune responses (
      • Disanto G.
      • Sacco R.
      • Bernasconi E.
      • et al.
      Association of Disease-Modifying Treatment and Anti-CD20 Infusion Timing With Humoral Response to 2 SARS-CoV-2 Vaccines in Patients With Multiple Sclerosis.
      )
      2022United Kingdom473 MS patientsB-cell depleting therapies, natalizumab, alemtuzumab, dimethyl fumarate, cladribine, glatiramer acetate, fingolimod, interferon beta, or teriflunomideChAdOx1 nCoV-1, BNT162b2, or Ad26.COV2.STreatment with fingolimod or B-cell depleting therapies is associated with low seroconversion rates (
      • Tallantyre E.C.
      • Vickaryous N.
      • Anderson V.
      • et al.
      COVID-19 Vaccine Response in People with Multiple Sclerosis.
      )
      2022United States80 study participants (13 health controls; 67 DMT-treated MS patients)Rituximab, ocrelizumab, glatiramer acetate, dimethyl fumarate, natalizumab, or S1P receptor modulatorsBNT162b2, Ad26.COV2.S, or mRNA-1273Significantly reduced immune responses were noted in cladribine- or S1P receptor modulator-treated MS patients following vaccination (
      • Sabatino Jr, J.J.
      • Mittl K.
      • Rowles W.M.
      • et al.
      Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.
      )
      2022Israel73 study participants (40 health controls; 33 MS patients)OcrelizumabBNT162b2Cytokine production by MS patients rivaled that of healthy controls shortly after vaccination (
      • Brill L.
      • Raposo C.
      • Rechtman A.
      • et al.
      SARS-CoV-2 third vaccine immune response in MS patients treated with ocrelizumab [published online ahead of print, 2022 Mar 4].
      ). Waning SARS-CoV-2-specific T-cell and humoral responses were noted in MS patients 6 months after 2nd dose (
      • Brill L.
      • Raposo C.
      • Rechtman A.
      • et al.
      SARS-CoV-2 third vaccine immune response in MS patients treated with ocrelizumab [published online ahead of print, 2022 Mar 4].
      ).
      2022Israel211 MS patientsInterferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab, fingolimod, ocrelizumab, alemtuzumab, cladribine, or rituximabBNT162b2Third vaccine dose is safe and effective for DMT-treated MS patients with no increased risk of disease relapse (
      • Dreyer-Alster S.
      • Menascu S.
      • Mandel M.
      • et al.
      COVID-19 vaccination in patients with multiple sclerosis: safety and humoral efficacy of the third booster dose.
      )
      2022United States and Denmark64 MS patientsOcrelizumabBNT162b2A 3rd vaccine dose did not lead to significantly greater humoral or cellular responses in ocrelizumab-treated MS patients (
      • Bajwa H.M.
      • Novak F.
      • Nilsson A.C.
      • et al.
      Persistently reduced humoral and sustained cellular immune response from first to third SARS-COV-2 mrna vaccination in anti-cd20-treated multiple sclerosis patients.
      )
      2022Switzerland27 MS patientsFingolimodBNT162b2 or mRNA-12734 of 8 patients treated with fingolimod demonstrated sufficient humoral immunity after 3rd vaccine dose (
      • Achtnichts L.
      • Ovchinnikov A.
      • Jakopp B.
      • et al.
      SARS-CoV-2 mRNA Vaccination in People with Multiple Sclerosis Treated with Fingolimod: protective Humoral Immune Responses May Develop after the Preferred Third Shot.
      )
      COVID-19: coronavirus disease 2019; MS: multiple sclerosis; S1P: sphingosine-1-phosphate.
      On the other hand, concerns of reduced COVID-19 vaccine immunogenicity in MS patients may be warranted given currently available data. A study involving 125 MS patients found that while both untreated and cladribine-treated MS patients exhibited humoral immune responses that rivaled those of healthy controls, ocrelizumab and fingolimod treatment was associated with markedly reduced rates of antibody development following BNT162b2 vaccination (Table 1) (
      • Achiron A.
      • Mandel M.
      • Dreyer-Alster S.
      • et al.
      Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.
      ). Two more recent studies reported similar findings; patients treated with fingolimod or anti-CD20 monoclonal antibody drugs were noted to exhibit significantly decreased rates of seroconversion after receiving an mRNA or adenovirus COVID-19 vaccine (Table 1) (
      • Tallantyre E.C.
      • Vickaryous N.
      • Anderson V.
      • et al.
      COVID-19 Vaccine Response in People with Multiple Sclerosis.
      ;
      • Sabatino Jr, J.J.
      • Mittl K.
      • Rowles W.M.
      • et al.
      Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.
      ). Both studies also observed that COVID-19 vaccines were similarly effective in untreated MS patients and those using glatiramer acetate, dimethyl fumarate, and natalizumab (
      • Tallantyre E.C.
      • Vickaryous N.
      • Anderson V.
      • et al.
      COVID-19 Vaccine Response in People with Multiple Sclerosis.
      ;
      • Sabatino Jr, J.J.
      • Mittl K.
      • Rowles W.M.
      • et al.
      Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.
      ). Altogether, these studies suggest that with the exception of fingolimod and B-cell depleting therapies, DMTs do not significantly impair humoral immune responses to the first and second doses of the Pfizer or Oxford-AstraZeneca vaccines. Additional studies will likely be needed to confirm the applicability of these findings to other COVID-19 vaccines.
      Despite the growing body of evidence that B-cell depleting therapies significantly reduce COVID-19 vaccine immunogenicity, vaccines may still prove useful in this patient population. Researchers have observed these individuals producing robust, antigen-specific CD4+ and CD8+ T cell responses after mRNA vaccination against SARS-CoV-2; in one study, cytokine production by stimulated SARS-CoV-2-specific CD8+ T cells was significantly greater in patients treated with rituximab or ocrelizumab than untreated patients (Table 1) (
      • Sabatino Jr, J.J.
      • Mittl K.
      • Rowles W.M.
      • et al.
      Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.
      ;
      • Apostolidis S.A.
      • Kakara M.
      • Painter M.M.
      • et al.
      Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.
      ;
      • Brill L.
      • Raposo C.
      • Rechtman A.
      • et al.
      SARS-CoV-2 third vaccine immune response in MS patients treated with ocrelizumab [published online ahead of print, 2022 Mar 4].
      ). Considering that better health outcomes have been associated with intact CD8+ T cell immunity in B-cell depleted COVID-19 patients, vaccinated patients using rituximab or ocrelizumab may still be capable of mounting sufficient T cell responses to SARS-CoV-2 and consequently less likely to experience severe COVID-19 infection (
      • Bange E.M.
      • Han N.A.
      • Wileyto P.
      • et al.
      CD8+ T cells contribute to survival in patients with COVID-19 and hematologic cancer.
      ). Further research is needed to characterize the precise role of T cells in COVID-19 infection, but given currently available data, MS patients treated with rituximab or ocrelizumab may benefit from vaccination via cell-mediated immunity.
      To promote long-term humoral immunity to SARS-CoV-2 and maintain antibody levels in patients months after initial vaccination, the administration of an additional (i.e. booster) dose of the COVID-19 vaccine has also been recommended. Preliminary data have revealed untreated MS patients and those receiving cladribine, dimethyl fumarate, natalizumab, teriflunomide, and glatiramer acetate infusions respond robustly to a third dose of the BNT162b2 vaccine (Table 1) (
      • Dreyer-Alster S.
      • Menascu S.
      • Mandel M.
      • et al.
      COVID-19 vaccination in patients with multiple sclerosis: safety and humoral efficacy of the third booster dose.
      ). There was also no notable increase in their rates of relapse (
      • Dreyer-Alster S.
      • Menascu S.
      • Mandel M.
      • et al.
      COVID-19 vaccination in patients with multiple sclerosis: safety and humoral efficacy of the third booster dose.
      ).
      Vaccination of patients relying on high-efficacy DMTs like ocrelizumab have not been nearly as successful. Studies conducted on B-cell depleted MS patients have noted minimal changes in seroconversion rates following a third mRNA vaccine dose and have rarely observed patients who were initially seronegative after two vaccine doses become seropositive (Table 1) (
      • Brill L.
      • Raposo C.
      • Rechtman A.
      • et al.
      SARS-CoV-2 third vaccine immune response in MS patients treated with ocrelizumab [published online ahead of print, 2022 Mar 4].
      ;
      • Bajwa H.M.
      • Novak F.
      • Nilsson A.C.
      • et al.
      Persistently reduced humoral and sustained cellular immune response from first to third SARS-COV-2 mrna vaccination in anti-cd20-treated multiple sclerosis patients.
      ;
      • Achtnichts L.
      • Jakopp B.
      • Oberle M.
      • et al.
      Humoral Immune Response after the Third SARS-CoV-2 mRNA Vaccination in CD20 Depleted People with Multiple Sclerosis.
      ). Patients on fingolimod have not fared much better; following a third mRNA vaccination, only 50% of MS patients on the sphingosine-1-phosphate receptor modulator achieved clinically significant IgG levels according to a Swiss study (Table 1) (
      • Achtnichts L.
      • Ovchinnikov A.
      • Jakopp B.
      • et al.
      SARS-CoV-2 mRNA Vaccination in People with Multiple Sclerosis Treated with Fingolimod: protective Humoral Immune Responses May Develop after the Preferred Third Shot.
      ). Altogether, these findings suggest that a third COVID-19 dose may be helpful in maintaining immunity in an already responsive minority of B-cell deficient patients but likely will not benefit most seronegative MS patients treated with ocrelizumab or fingolimod.
      Moreover, modifications to a patient's COVID-19 immunization schedule and DMT regimen have been suggested as means to optimize vaccine efficacy. Specifically, the Swiss Multiple Sclerosis Society has recommended that a third COVID-19 vaccine be given to MS patients ahead of schedule to enhance seroconversion rates, a recommendation that likely arose from recent reports of diminishing vaccine-induced immunity over time and clinical benefits of a third dose (;
      • Levin E.G.
      • Lustig Y.
      • Cohen C.
      • et al.
      Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months.
      ;
      • Bar-On Y.M.
      • Goldberg Y.
      • Mandel M.
      • et al.
      Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel.
      ;
      • Patalon T.
      • Gazit S.
      • Pitzer V.E.
      • Prunas O.
      • Warren J.L.
      • Weinberger D.M.
      Odds of testing positive for SARS-CoV-2 following receipt of 3 vs 2 doses of the BNT162b2 mRNA vaccine.
      ). Delaying the infusion of anti-CD20 therapy before vaccination is also believed to maximize humoral immune response (
      • Cabreira V.
      • Abreu P.
      • Soares-dos-Reis R.
      • Guimarães J.
      • Sá M.J.
      Multiple sclerosis, disease-modifying therapies and COVID-19: a systematic review on immune response and vaccination recommendations.
      ). Levels of SARS-CoV-2-specific antibodies have been observed to progressively rise with longer spans of time between last infusion and vaccine dose, with significant differences emerging after 6 months according to a systematic review (Table 1) (
      • Sormani M.P.
      • Inglese M.
      • Schiavetti I.
      • et al.
      Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
      ;
      • Schietzel S.
      • Anderegg M.
      • Limacher A.
      • et al.
      Humoral and cellular immune responses on SARS-CoV-2 vaccines in patients with anti-CD20 therapies: a systematic review and meta-analysis of 1342 patients.
      ;
      • Disanto G.
      • Sacco R.
      • Bernasconi E.
      • et al.
      Association of Disease-Modifying Treatment and Anti-CD20 Infusion Timing With Humoral Response to 2 SARS-CoV-2 Vaccines in Patients With Multiple Sclerosis.
      ). This approach may be feasible and safe as recent studies have shown lengthening time between ocrelizumab or rituximab infusions by more than 7 months does not lead to significantly higher relapse rates or greater disease activity (
      • Rolfes L.
      • Pawlitzki M.
      • Pfeuffer S.
      • et al.
      Ocrelizumab Extended Interval Dosing in Multiple Sclerosis in Times of COVID-19.
      ;
      • Maarouf A.
      • Rico A.
      • Boutiere C.
      • et al.
      Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond?.
      ). With these findings in mind, physicians could help enhance vaccine efficacy in MS patients by making individualized modifications to a patient's vaccine schedule and DMT regimen.
      Vaccination guidelines for MS patients and physicians have also been published by various organizations and societies. The American Academy of Neurology, Multiple Sclerosis International Federation (MSIF), National Multiple Sclerosis Society (NMSS), and European Committee for Treatment and Research in Multiple Sclerosis have all strongly recommended that patients with MS receive vaccination against SARS-CoV-2 (
      • Marsh E.B.
      • Kornberg M.
      • Kessler K.
      • et al.
      COVID-19 and Vaccination in the Setting of Neurologic Disease: an Emerging Issue in Neurology.
      ; ; ;
      • Lee S
      EAN Joint Session at 37th ECTRIMS Congress to Focus on Vaccination and Treatment Guidelines for People with Multiple Sclerosis.
      ;
      The Coronavirus and MS
      Updated Global Advice.
      ). Most, if not all, patients are encouraged to receive any of the available COVID-19 vaccines, continue their DMTs, and regardless of vaccination status, engage in additional precautionary measures such as social distancing, masking, and frequent handwashing (
      • Marsh E.B.
      • Kornberg M.
      • Kessler K.
      • et al.
      COVID-19 and Vaccination in the Setting of Neurologic Disease: an Emerging Issue in Neurology.
      ; ; ;
      • Lee S
      EAN Joint Session at 37th ECTRIMS Congress to Focus on Vaccination and Treatment Guidelines for People with Multiple Sclerosis.
      ;
      The Coronavirus and MS
      Updated Global Advice.
      ). The findings of the studies reviewed above largely support these recommendations, particularly in the case of patients relying on high-efficacy DMTs who may mount suboptimal humoral immune responses after vaccination and therefore should exercise extreme caution (
      • Achiron A.
      • Mandel M.
      • Dreyer-Alster S.
      • et al.
      Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.
      ;
      • Tallantyre E.C.
      • Vickaryous N.
      • Anderson V.
      • et al.
      COVID-19 Vaccine Response in People with Multiple Sclerosis.
      ;
      • Sabatino Jr, J.J.
      • Mittl K.
      • Rowles W.M.
      • et al.
      Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.
      ). The MSIF and NMSS have even mentioned the possibility of altering the timing of DMT infusions as a means of optimizing vaccine efficacy, a strategy that has been demonstrated to be feasible, safe, and effective in previously mentioned studies (
      • Sormani M.P.
      • Inglese M.
      • Schiavetti I.
      • et al.
      Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
      ;
      • Schietzel S.
      • Anderegg M.
      • Limacher A.
      • et al.
      Humoral and cellular immune responses on SARS-CoV-2 vaccines in patients with anti-CD20 therapies: a systematic review and meta-analysis of 1342 patients.
      ;
      • Disanto G.
      • Sacco R.
      • Bernasconi E.
      • et al.
      Association of Disease-Modifying Treatment and Anti-CD20 Infusion Timing With Humoral Response to 2 SARS-CoV-2 Vaccines in Patients With Multiple Sclerosis.
      ;
      • Rolfes L.
      • Pawlitzki M.
      • Pfeuffer S.
      • et al.
      Ocrelizumab Extended Interval Dosing in Multiple Sclerosis in Times of COVID-19.
      ;
      • Maarouf A.
      • Rico A.
      • Boutiere C.
      • et al.
      Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond?.
      ; ;
      The Coronavirus and MS
      Updated Global Advice.
      ).

      4. Influenza vaccine

      Although the safety of the influenza vaccine in MS patients has been extensively studied and its potential adverse effects thoroughly characterized, there have been a limited number of studies investigating the immunogenic responses of MS patients to these vaccines. We recently published a systematic review and meta-analysis providing insight into the immunogenicity of influenza vaccines in MS patients. Our study evaluated the immunogenicity of vaccinated MS patients via measured seroconversion and seroprotection in comparison to those of healthy controls (
      • Nguyen J.
      • Hardigan P.
      • Kesselman M.M.
      • Demory Beckler M
      Immunogenicity of The Influenza Vaccine in Multiple Sclerosis Patients: a Systematic Review and Meta-Analysis.
      ). Of the nine total studies, five measured the immune responses of MS patients to vaccines for the H1N1 strain of influenza A (
      • Olberg H.K.
      • Cox R.J.
      • Nostbakken J.K.
      • Aarseth J.H.
      • Vedeler C.A.
      • Myhr K.M.
      Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study.
      ;
      • Olberg H.K.
      • Eide G.E.
      • Cox R.J.
      • et al.
      Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy.
      ;
      • Mokhtarian F.
      • Shirazian D.
      • Morgante L.
      • Miller A.
      • Grob D.
      • Lichstein E.
      Influenza virus vaccination of patients with multiple sclerosis.
      ;
      • Kim W.
      • Kim S.H.
      • Huh S.Y.
      • et al.
      Reduced antibody formation after influenza vaccination in patients with neuromyelitis optica spectrum disorder treated with rituximab.
      ). Most notably, rates of protection imparted by this vaccine were not observed to be significantly different between MS patients and their healthy counterparts (
      • Nguyen J.
      • Hardigan P.
      • Kesselman M.M.
      • Demory Beckler M
      Immunogenicity of The Influenza Vaccine in Multiple Sclerosis Patients: a Systematic Review and Meta-Analysis.
      ).
      In three of the five studies, interferon-β use in MS patients was not associated with significantly decreased immune responses, a finding that is largely consistent with an earlier, independently conducted study involving a smaller cohort (
      • Nguyen J.
      • Hardigan P.
      • Kesselman M.M.
      • Demory Beckler M
      Immunogenicity of The Influenza Vaccine in Multiple Sclerosis Patients: a Systematic Review and Meta-Analysis.
      ;
      • Metze C.
      • Winkelmann A.
      • Loebermann M.
      • et al.
      Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease-modifying therapies.
      ). MS patients relying on DMTs including glatiramer acetate, natalizumab, and mitoxantrone were noted by one study to exhibit reduced long-term protection from influenza infection, while another study determined the rates of protection in vaccinated MS patients receiving interferon, natalizumab, or glatiramer acetate treatment to be statistically indistinguishable from those of healthy controls (
      • Olberg H.K.
      • Cox R.J.
      • Nostbakken J.K.
      • Aarseth J.H.
      • Vedeler C.A.
      • Myhr K.M.
      Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study.
      ;
      • Olberg H.K.
      • Eide G.E.
      • Cox R.J.
      • et al.
      Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy.
      ). Altogether, pooling of the data from both studies as well as several others revealed an absence of treatment effects on the immunogenicity of the H1N1 vaccine in MS patients (
      • Nguyen J.
      • Hardigan P.
      • Kesselman M.M.
      • Demory Beckler M
      Immunogenicity of The Influenza Vaccine in Multiple Sclerosis Patients: a Systematic Review and Meta-Analysis.
      ).
      Four of the nine studies measured immune responses of MS patients to vaccines for the H3N2 strain of influenza A (
      • Olberg H.K.
      • Cox R.J.
      • Nostbakken J.K.
      • Aarseth J.H.
      • Vedeler C.A.
      • Myhr K.M.
      Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study.
      ;
      • Olberg H.K.
      • Eide G.E.
      • Cox R.J.
      • et al.
      Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy.
      ;
      • Mokhtarian F.
      • Shirazian D.
      • Morgante L.
      • Miller A.
      • Grob D.
      • Lichstein E.
      Influenza virus vaccination of patients with multiple sclerosis.
      ;
      • Moriabadi N.F.
      • Niewiesk S.
      • Kruse N.
      • et al.
      Influenza vaccination in MS: absence of T-cell response against white matter proteins.
      ). In all four studies, antibody titers in these patients were found to be significantly higher following vaccination and comparable to those of their healthy, vaccinated counterparts (
      • Nguyen J.
      • Hardigan P.
      • Kesselman M.M.
      • Demory Beckler M
      Immunogenicity of The Influenza Vaccine in Multiple Sclerosis Patients: a Systematic Review and Meta-Analysis.
      ). However, one study observed that vaccinated MS patients using glatiramer acetate, natalizumab, and mitoxantrone exhibited lower rates of protection than those relying solely upon interferon-β for disease management at six months post-vaccination (
      • Olberg H.K.
      • Cox R.J.
      • Nostbakken J.K.
      • Aarseth J.H.
      • Vedeler C.A.
      • Myhr K.M.
      Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study.
      ). Another study led by the same researcher reported similar findings; all vaccinated MS patients receiving any DMTs were determined to be protected at significantly lower levels than healthy controls (
      • Olberg H.K.
      • Eide G.E.
      • Cox R.J.
      • et al.
      Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy.
      ).
      In addition, we found adequate immune responses were elicited in MS patients after receiving vaccines for influenza A strains using data from three studies (
      • Nguyen J.
      • Hardigan P.
      • Kesselman M.M.
      • Demory Beckler M
      Immunogenicity of The Influenza Vaccine in Multiple Sclerosis Patients: a Systematic Review and Meta-Analysis.
      ;
      • Vagberg M.
      • Kumlin U.
      • Svenningsson A.
      Humoral immune response to influenza vaccine in natalizumab-treated MS patients.
      ;
      • Mehling M.
      • Fritz S.
      • Hafner P.
      • et al.
      Preserved antigen-specific immune response in patients with multiple sclerosis responding to IFNbeta-therapy.
      ;
      • Mehling M.
      • Hilbert P.
      • Fritz S.
      • et al.
      Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients.
      ). Another three studies confirmed comparable humoral immune responses were achieved in MS patients vaccinated for influenza B strains (
      • Mokhtarian F.
      • Shirazian D.
      • Morgante L.
      • Miller A.
      • Grob D.
      • Lichstein E.
      Influenza virus vaccination of patients with multiple sclerosis.
      ;
      • Mehling M.
      • Fritz S.
      • Hafner P.
      • et al.
      Preserved antigen-specific immune response in patients with multiple sclerosis responding to IFNbeta-therapy.
      ;
      • Mehling M.
      • Hilbert P.
      • Fritz S.
      • et al.
      Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients.
      ). After pooling all the data, significant effects of treatment on the immune responses of MS patients to H3N2, influenza A, and influenza B vaccines were ultimately not found (
      • Nguyen J.
      • Hardigan P.
      • Kesselman M.M.
      • Demory Beckler M
      Immunogenicity of The Influenza Vaccine in Multiple Sclerosis Patients: a Systematic Review and Meta-Analysis.
      ).
      Though several studies have observed treatment effects on the immunogenicity of influenza vaccines in MS patients, our study and others suggest that the observed differences are not statistically significant (
      • Kappos L.
      • Mehling M.
      • Arroyo R.
      • et al.
      Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis.
      ;
      • Nguyen J.
      • Hardigan P.
      • Kesselman M.M.
      • Demory Beckler M
      Immunogenicity of The Influenza Vaccine in Multiple Sclerosis Patients: a Systematic Review and Meta-Analysis.
      ;
      • Olberg H.K.
      • Eide G.E.
      • Cox R.J.
      • et al.
      Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy.
      ;
      • Metze C.
      • Winkelmann A.
      • Loebermann M.
      • et al.
      Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease-modifying therapies.
      ). Based on these most recent findings, it appears vaccinated MS patients can mount adequate immune responses and demonstrate similar rates of protection from influenza as compared to the general population, regardless of DMT use. Future studies that rely on larger sample sizes and control for confounding variables such as sex, age, ethnicity, and comorbidities will likely lend further support to these findings and provide invaluable insight into the potential effects of DMTs on the immunogenicity of influenza vaccines in MS patients.

      5. Hepatitis B virus (HBV) vaccine

      HBV poses a pressing health risk to populations worldwide, affecting over 2 billion individuals and causing chronic infection in an estimated 360 million patients (
      • Lavanchy D.
      Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures.
      ;
      • Shepard C.W.
      • Simard E.P.
      • Finelli L.
      • Fiore A.E.
      • Bell B.P.
      Hepatitis B virus infection: epidemiology and vaccination.
      ). With the advent of HBV surface antigen-containing vaccines, rates of chronic infection and HBV-related complications, like hepatocellular carcinoma, have dropped significantly; the Centers for Disease Control and Prevention currently recommends infants, adolescents, and adults to undergo vaccination unless patients have a history of allergic reactions to any vaccine components (
      • Shouval D
      Hepatitis B vaccines.
      ;

      Hepatitis B., FAQs, Statistics, Data, & Guidelines. Centers for Disease Control and Prevention. https://www.cdc.gov/hepatitis/hbv/index.htm Published October 12, 2021. Accessed March 15, 2022.

      ). Though exceedingly safe in the general population, vaccination against HBV has raised concerns regarding its potential to cause MS and exacerbate its symptoms. These concerns were largely driven by early reports of patients with MS and otherwise healthy adults developing demyelinating lesions after vaccination (
      • Herroelen L.
      • de Keyser J.
      • Ebinger G.
      Central-nervous-system demyelination after immunisation with recombinant hepatitis B vaccine.
      ;
      • Tourbah A.
      • Gout O.
      • Liblau R.
      • et al.
      Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS?.
      ). However, subsequent case-control studies failed to establish a link between HBV vaccination and elevated MS risk in adolescents and adults (
      • DeStefano F.
      • Verstraeten T.
      • Jackson L.A.
      • et al.
      Vaccinations and risk of central nervous system demyelinating diseases in adults.
      ;
      • Mikaeloff Y.
      • Caridade G.
      • Rossier M.
      • Suissa S.
      • Tardieu M.
      Hepatitis B vaccination and the risk of childhood-onset multiple sclerosis.
      ;
      • Ascherio A.
      • Zhang S.M.
      • Hernán M.A.
      • et al.
      Hepatitis B vaccination and the risk of multiple sclerosis.
      ). A prospective study also observed an increased MS risk following live vaccination against HBV, but their findings have been inconsistent with the existing literature (
      • Hernán M.A.
      • Jick S.S.
      • Olek M.J.
      • Jick H.
      Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study.
      ). Namely, a case-crossover study found no association between HBV vaccination and risk of MS development or exacerbation (
      • Confavreux C.
      • Suissa S.
      • Saddier P.
      • Bourdès V.
      • Vukusic S.
      Vaccines in Multiple Sclerosis Study Group. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group.
      ). Recent systematic reviews have supported these findings, confirming that there is little to no evidence that HBV vaccination increases MS risk or causes relapse (
      • Sestili C.
      • Grazina I.
      • La Torre G
      HBV vaccine and risk of developing multiple sclerosis: a systematic review and meta-analysis.
      ;
      • Mailand M.T.
      • Frederiksen J.L.
      Vaccines and multiple sclerosis: a systematic review.
      ). Like influenza vaccines, those against HBV are likely both effective and safe in MS patients and the general population.
      The use of DMTs in MS patients with chronic HBV infections, however, is not without risks. Reports of HBV reactivation in patients using alemtuzumab, fingolimod, natalizumab, and ocrelizumab suggest that HBV screening is essential in this patient population prior to DMT administration (
      • Lu M.C.
      • Shih Y.L.
      • Hsieh T.Y.
      • Lin J.C.
      Flare of hepatitis B virus after fingolimod treatment for relapsing and remitting multiple sclerosis.
      ;
      • Hillen M.E.
      • Cook S.D.
      • Samanta A.
      • Grant E.
      • Quinless J.R.
      • Rajasingham J.K.
      Fatal acute liver failure with hepatitis B virus infection during nataluzimab treatment in multiple sclerosis.
      ;
      • Ciardi M.R.
      • Iannetta M.
      • Zingaropoli M.A.
      • et al.
      Reactivation of Hepatitis B Virus With Immune-Escape Mutations After Ocrelizumab Treatment for Multiple Sclerosis.
      ;
      • Iannitto E.
      • Minardi V.
      • Calvaruso G.
      • et al.
      Hepatitis B virus reactivation and alemtuzumab therapy.
      ). As such, prudent management, and screening of DMT-dependent MS patients with latent HBV infections are necessary to prevent complications and promote long-term health.

      6. Measles, mumps, and rubella vaccine

      Measles, mumps, and rubella are viral infections that can be prevented by the highly efficacious MMR vaccine (
      • Bankamp B.
      • Hickman C.
      • Icenogle J.P.
      • Rota P.A.
      Successes and challenges for preventing measles, mumps and rubella by vaccination.
      ). Measles, a member of the Paramyxoviridae family, is typically spread by inhalation of respiratory droplets and causes fever, a maculopapular rash, cough, coryza, and conjunctivitis (
      • Bankamp B.
      • Hickman C.
      • Icenogle J.P.
      • Rota P.A.
      Successes and challenges for preventing measles, mumps and rubella by vaccination.
      ). Mumps, another member of the Paramyxovirdae family, typically causes orchitis, encephalitis, and meningitis, as well as fever, swelling, and tenderness of the salivary glands (
      • Bankamp B.
      • Hickman C.
      • Icenogle J.P.
      • Rota P.A.
      Successes and challenges for preventing measles, mumps and rubella by vaccination.
      ). Finally, rubella, a member of the Togaviridae family, is spread through sneezing or coughing, and causes a generalized maculopapular rash, fever, arthritis, lymphadenopathy, and conjunctivitis. If acquired in-utero, cataracts, cardiac abnormalities, and deafness can result (
      • Bankamp B.
      • Hickman C.
      • Icenogle J.P.
      • Rota P.A.
      Successes and challenges for preventing measles, mumps and rubella by vaccination.
      ).
      To prevent these childhood viral illnesses, the live-attenuated MMR vaccine was first introduced in 197194. The vaccine is typically given in two doses to children but may also be administered to adults (
      • Bailey A.
      • Sapra A
      MMR Vaccine. In: StatPearls. Treasure Island (FL).
      ). Between 2010 and 2015, global measles vaccination is estimated to have prevented more than 20 million deaths and decreased the measles incidence from 146 to 36 cases per million populations (
      • Kowalzik F.
      • Faber J.
      • Knuf M.
      MMR and MMRV vaccines.
      ). The MMR vaccine is typically regarded as immunogenic and safe (
      • Bailey A.
      • Sapra A
      MMR Vaccine. In: StatPearls. Treasure Island (FL).
      ).
      Interestingly, an association between childhood illnesses and the development of MS has been identified. Childhood viral infections may play a role in MS development, as they may increase the risk of developing MS substantially (
      • Eftekharian M.M.
      • Ghannad M.S.
      • Taheri M.
      • et al.
      Frequency of viral infections and environmental factors in multiple sclerosis.
      ). Therefore, MMR vaccine administration is imperative. However, several cases of optic neuritis were observed following the MMR vaccine, thought to be associated with the toxic reactivation of the non-viral component of the vaccine (
      • De Giacinto C.
      • Guaglione E.
      • Leon P.E.
      • et al.
      Unilateral Optic Neuritis: a Rare Complication after Measles-Mumps-Rubella Vac.cination in a 30-Year-Old Woman.
      ;
      • Riikonen R.
      The role of infection and vaccination in the genesis of optic neuritis and multiple sclerosis in children.
      ). All but one case subsequently developed MS (
      • Riikonen R.
      The role of infection and vaccination in the genesis of optic neuritis and multiple sclerosis in children.
      ). There were also several cases of transverse myelitis following MMR vaccine (
      • Joyce K.A.
      • Rees J.E.
      Transverse myelitis after measles, mumps, and rubella vaccine.
      ;
      • Lim S.
      • Park S.M.
      • Choi H.S.
      • et al.
      Transverse myelitis after measles and rubella vaccination.
      ). Of note, MS can develop 7–10 years after an acute demyelinating attack and thus, there may be limited use of the aforementioned studies. (
      • De Giacinto C.
      • Guaglione E.
      • Leon P.E.
      • et al.
      Unilateral Optic Neuritis: a Rare Complication after Measles-Mumps-Rubella Vac.cination in a 30-Year-Old Woman.
      ;
      • Riikonen R.
      The role of infection and vaccination in the genesis of optic neuritis and multiple sclerosis in children.
      ;
      • Joyce K.A.
      • Rees J.E.
      Transverse myelitis after measles, mumps, and rubella vaccine.
      ;
      • Lim S.
      • Park S.M.
      • Choi H.S.
      • et al.
      Transverse myelitis after measles and rubella vaccination.
      ) Nonetheless, several studies have since aimed to understand if there is an association with the MMR vaccine and the development of MS and all but one have returned negative (
      • DeStefano F.
      • Verstraeten T.
      • Jackson L.A.
      • et al.
      Vaccinations and risk of central nervous system demyelinating diseases in adults.
      ;
      • Zorzon M.
      • Zivadinov R.
      • Nasuelli D.
      • et al.
      Risk factors of multiple sclerosis: a case-control study.
      ;
      • Ramagopalan S.V.
      • Valdar W.
      • Dyment D.A.
      • et al.
      Association of infectious mononucleosis with multiple sclerosis. A population-based study.
      ;
      • Ahlgren C.
      • Odén A.
      • Torén K.
      • Andersen O.
      Multiple sclerosis incidence in the era of measles-mumps-rubella mass vaccinations.
      ;
      • Ahlgren C.
      • Torén K.
      • Odén A.
      • Andersen O.
      A population-based case-control study on viral infections and vaccinations and subsequent multiple sclerosis risk.
      ;
      • Farez M.F.
      • Correale J.
      Immunizations and risk of multiple sclerosis: systematic review and meta-analysis.
      ) The singular study that did find an association had a relatively small sample size, however (
      • Zorzon M.
      • Zivadinov R.
      • Nasuelli D.
      • et al.
      Risk factors of multiple sclerosis: a case-control study.
      ).
      It is largely recommended that individuals with MS be tested for immunity to measles, mumps, and rubella prior to starting immunosuppressive therapies (
      • Reyes S.
      • Ramsay M.
      • Ladhani S.
      • et al.
      Protecting people with multiple sclerosis through vaccination.
      ). If the individual is not currently immune, MMR vaccine administration is recommended (
      • Reyes S.
      • Ramsay M.
      • Ladhani S.
      • et al.
      Protecting people with multiple sclerosis through vaccination.
      ). However, because the MMR vaccine is a live-attenuated vaccine, administration should be avoided for those who are currently taking disease modifying, immunosuppressive therapy (
      • Lebrun C.
      Vukusic S; French Group for Recommendations in Multiple Sclerosis (France4MS) and the Société Francophone de la Sclérose En Plaques (SFSEP). Immunization and multiple sclerosis: recommendations from the French multiple sclerosis society.
      ).

      7. Human papillomavirus (HPV) vaccine

      HPV is one of the most common sexually transmitted diseases worldwide, affecting more than 42.5 million people in America alone (
      • Wang R.
      • Pan W.
      • Jin L.
      • et al.
      Human papillomavirus vaccine against cervical cancer: opportunity and challenge.
      ;

      Sexually Transmitted Infections Prevalence, Incidence, and Cost Estimates in the United States. Centers for Disease Control and Prevention. https://www.cdc.gov/std/statistics/prevalence-2020-at-a-glance.htm. Published January 25, 2021. Accessed March 15, 2022.

      ). HPV typically infects squamous cell epithelium and is thereby largely associated with cutaneous and anogenital warts as well as various neoplastic illnesses, such as cervical, vulvar and vaginal cancer in women; penile cancer in men; and anal and mucosal cancers in both sexes (
      • Wang R.
      • Pan W.
      • Jin L.
      • et al.
      Human papillomavirus vaccine against cervical cancer: opportunity and challenge.
      ;
      • Pagliusi S.R.
      • Garland S.M.
      International standard reagents for HPV detection.
      ). While there are hundreds of HPV subtypes, less than a dozen are referred to as high risk - most common of which are HPV 16 and 18 (
      • Wang R.
      • Pan W.
      • Jin L.
      • et al.
      Human papillomavirus vaccine against cervical cancer: opportunity and challenge.
      ).
      Currently, there are 3 types of HPV vaccines, quadrivalent, bivalent, and nonavalent, that prevent around 90% of cancers caused by HPV (
      • Wang R.
      • Pan W.
      • Jin L.
      • et al.
      Human papillomavirus vaccine against cervical cancer: opportunity and challenge.
      ;
      • Petrosky E.
      • Bocchini Jr, J.A.
      • Hariri S.
      • et al.
      Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices.
      ). Each vaccine is a noninfectious, virus-like particle (VLP) vaccine (
      HPV
      the Vaccine for HPV, and Cancers Caused By HPV.
      ). As of 2015, the World Health Organization (WHO) recommends two doses of the nonavalent HPV vaccine in individuals under the age of 15, and three doses for those 15 and older (
      • Harper D.M.
      • DeMars L.R.
      HPV vaccines - A review of the first decade.
      ). It is believed that the vaccine can provide prevention for HPV and HPV-related cancers until the individual enters the age of routine preventative screening (
      • Harper D.M.
      • DeMars L.R.
      HPV vaccines - A review of the first decade.
      ).
      While the HPV vaccine's efficacy has largely been elucidated, the utility of the vaccine in the MS population is still controversial (
      • Meggiolaro A.
      • Migliara G.
      • La Torre G
      Association between Human Papilloma Virus (HPV) vaccination and risk of Multiple Sclerosis: a systematic review.
      ). A 2014 nested control study found an increased risk of CNS acquired demyelinating syndrome (ADS) within the first 30 days after HPV vaccination in individuals under 50 years old, thought to be attributed to a vaccine induced acceleration from subclinical to autoimmunity (
      • Langer-Gould A.
      • Qian L.
      • Tartof S.Y.
      • et al.
      Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases.
      ). No long-term effect was determined, however (
      • Langer-Gould A.
      • Qian L.
      • Tartof S.Y.
      • et al.
      Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases.
      ). Sutton and his team reported of five patients who presented with demyelinating syndromes 21 days after receiving the quadrivalent HPV vaccine (
      • Sutton I.
      • Lahoria R.
      • Tan I.
      • Clouston P.
      • Barnett M.
      CNS demyelination and quadrivalent HPV vaccination.
      ). Nonetheless, countless studies have since concluded against an association between the HPV vaccine and the development of MS and other ADS. A 2018 systematic review found no association between the quadrivalent HPV vaccine and the risk for MS and other ADS (
      • Meggiolaro A.
      • Migliara G.
      • La Torre G
      Association between Human Papilloma Virus (HPV) vaccination and risk of Multiple Sclerosis: a systematic review.
      ). Further studies have largely agreed (
      • Langer-Gould A.
      • Qian L.
      • Tartof S.Y.
      • et al.
      Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases.
      ;
      • Scheller N.M.
      • Svanström H.
      • Pasternak B.
      • et al.
      Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system.
      ;
      • Grimaldi-Bensouda L.
      • Rossignol M.
      • Koné-Paut I.
      • et al.
      Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: six years of case-referent surveillance.
      ;
      • Pellegrino P.
      • Carnovale C.
      • Perrone V.
      • et al.
      No evidence of a link between multiple sclerosis and the vaccine against the human papillomavirus.
      ).
      Fingolimod is a strong immunosuppressive and immunomodulating agent frequently prescribed to individuals with relapsing remitting MS (RR-MS) (
      • Triplett J.
      • Kermode A.G.
      • Corbett A.
      • Reddel S.W.
      Warts and all: fingolimod and unusual HPV-associated lesions.
      ;
      • Lorvik K.B.
      • Bogen B.
      • Corthay A.
      Fingolimod blocks immunosurveillance of myeloma and B-cell lymphoma resulting in cancer development in mice.
      ). Its relationship to HPV and the HPV vaccine is a recent field of research (
      • Triplett J.
      • Kermode A.G.
      • Corbett A.
      • Reddel S.W.
      Warts and all: fingolimod and unusual HPV-associated lesions.
      ;
      • Lorvik K.B.
      • Bogen B.
      • Corthay A.
      Fingolimod blocks immunosurveillance of myeloma and B-cell lymphoma resulting in cancer development in mice.
      ). Associations have been made between fingolimod and chronic treatment resistant HPV and HPV-related malignancies in a case series of 5 patients (
      • Triplett J.
      • Kermode A.G.
      • Corbett A.
      • Reddel S.W.
      Warts and all: fingolimod and unusual HPV-associated lesions.
      ). Improvement in those patients was observed following reduction or cessation of the medication (
      • Triplett J.
      • Kermode A.G.
      • Corbett A.
      • Reddel S.W.
      Warts and all: fingolimod and unusual HPV-associated lesions.
      ). It has been speculated that the risk of HPV-related malignancies in MS patients treated with DMTs increases due to decreased T-cell immunity (
      • Benedetti M.D.
      • Marangi A.
      • Bozzetti S.
      • et al.
      HPV-related papillary squamous cell carcinoma of the tonsil during treatment with fingolimod.
      ). Nevertheless, considering the anecdotal nature of these studies, no change in current vaccination policy is warranted (). Use of the HPV vaccine should be preceded with a conversation about the risks and benefits of vaccination (). It is also currently advised to take a thorough medical history of HPV, HPV-related malignancies, and HPV vaccination status prior to starting fingolimod in patients with MS (
      • Triplett J.
      • Kermode A.G.
      • Corbett A.
      • Reddel S.W.
      Warts and all: fingolimod and unusual HPV-associated lesions.
      ).

      8. Streptococcus pneumoniae vaccine

      Streptococcus pneumoniae, the most common cause of both overall pneumonia and fatal pneumonia, is most common in children under the age of 2 and adults older than 65 years old (
      • Ortqvist A.
      • Hedlund J.
      • Kalin M.
      Streptococcus pneumoniae: epidemiology, risk factors, and clinical features.
      ). Antibiotic resistance has developed over time and is most common in serotypes 6, 15, 19, 23, all of which are extremely common in children (
      • Ortqvist A.
      • Hedlund J.
      • Kalin M.
      Streptococcus pneumoniae: epidemiology, risk factors, and clinical features.
      ).
      There are currently two types of pneumococcal vaccines available in the United: conjugate vaccines and polysaccharide vaccines. The 23-valent capsular polysaccharide vaccine (PPSV23) was the first pneumococcal vaccine developed and is now primarily used as single dose after a 13-valent pneumococcal conjugate vaccine (PCV13) series in children ages 2–18 with certain medical conditions like sickle cell disease (
      • Daniels C.C.
      • Rogers P.D.
      • Shelton C.M.
      A Review of Pneumococcal vaccines: current polysaccharide vaccine recommendations and future protein antigens.
      ). The PCV13 is available for children younger than 2 years old, and children between the ages of 2 and 18 with certain medical conditions (
      Pneumococcal vaccination
      Centers For Disease Control and Prevention.
      ). Finally, the PCV15 and PCV20 are other approved conjugate pneumococcal vaccines recommended for adults 65 years old as well as adults ages 19–64 with certain medical conditions or risk factors (
      Pneumococcal vaccination
      Centers For Disease Control and Prevention.
      ).
      Individuals with MS on DMTs may have varied immune responses to pneumococcal vaccines. One study found that individuals on ocrelizumab had an attenuated reaction to non-live vaccines, including the pneumococcal vaccine, at 4 weeks, compared to those on interferon-β or untreated patients (
      • Bar-Or A.
      • Calkwood J.C.
      • Chognot C.
      • et al.
      Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study.
      ). Conversely, a small historically controlled pilot study concluded that immunocompetence was maintained after use of alemtuzumab, a humanized monoclonal antibody used to treat active RR-MS by targeting CD52 and causing depletion of T and B lymphocytes (
      • McCarthy C.L.
      • Tuohy O.
      • Compston D.A.
      • Kumararatne D.S.
      • Coles A.J.
      • Jones J.L.
      Immune competence after alemtuzumab treatment of multiple sclerosis.
      ;
      • Havrdova E.
      • Horakova D.
      • Kovarova I.
      Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use.
      ). However, poor responses were observed when various vaccines were given within 2 months of alemtuzumab treatment, suggesting that immunization very early after alemtuzumab treatment may not be effective (
      • McCarthy C.L.
      • Tuohy O.
      • Compston D.A.
      • Kumararatne D.S.
      • Coles A.J.
      • Jones J.L.
      Immune competence after alemtuzumab treatment of multiple sclerosis.
      ). Based on these data, current guidelines put forth by the United Kingdom recommend that people with MS ideally receive PPV23 at least 2 weeks before starting maintenance immunosuppressive and immune reconstitution therapies (
      • Reyes S.
      • Ramsay M.
      • Ladhani S.
      • et al.
      Protecting people with multiple sclerosis through vaccination.
      ). Additionally, those that are extremely immunocompromised should be offered the PCV13 at least 8 weeks before PPV23 (
      • Reyes S.
      • Ramsay M.
      • Ladhani S.
      • et al.
      Protecting people with multiple sclerosis through vaccination.
      ).

      9. Yellow fever vaccine

      Yellow fever, a potentially fatal vector-borne disease caused by the yellow fever virus (YFV), affects approximately 200,000 people annually (
      • Staples J.E.
      • Gershman M.
      • Fischer M.
      Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ). Part of the genus flavivirus, YFV is a small enveloped positive sense single-stranded RNA virus that is endemic to Sub-Saharan Africa and tropical South America. YFV is typically transmitted by a bite of a YFV-infected mosquito (
      • Staples J.E.
      • Gershman M.
      • Fischer M.
      Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ;
      • Monath T.P.
      Yellow fever vaccine.
      ). Though it commonly causes fever, chills, severe headache, and back pain, in severe cases, it may progress to a hemorrhagic fever that is fatal in 20–50% of cases (
      • Staples J.E.
      • Gershman M.
      • Fischer M.
      Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ). At the present time, there is no curative treatment (
      • Staples J.E.
      • Gershman M.
      • Fischer M.
      Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ). Accordingly, prevention is key.
      Current recommendations for the YFV vaccine in the general population is a single dose of a live-attenuated vaccine for individuals 9 months or older who are traveling to or living in high risk areas (
      • Staples J.E.
      • Gershman M.
      • Fischer M.
      Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ;
      Yellow Fever Vaccine
      Centers For Disease Control and Prevention.
      ). Recommendations for those with MS remain controversial due to findings of recent studies. A 2011 study found a significant increase in exacerbation rates within 3 months following the YFV vaccine compared to pre-vaccination exacerbation rates (
      • Farez M.F.
      • Correale J.
      Yellow fever vaccination and increased relapse rate in travelers with multiple sclerosis.
      ). Of note, since its publication, the methodology of the aforementioned study has been called into question (
      • Pool V.
      • Gordon D.M.
      • Decker M.
      Methodological issues with the risk of relapse study in patients with multiple sclerosis after yellow fever vaccination.
      ). On the other hand, a case series found no association between MS relapses and YFV vaccination (
      • Huttner A.
      • Eperon G.
      • Lascano A.M.
      • et al.
      Risk of MS relapse after yellow fever vaccination: a self-controlled case series.
      ). Subsequent studies have found no change in first relapse between individuals with RR-MS who were “exposed” to the YFV vaccine when compared to individuals with RR-MS who were “non-exposed (
      • Papeix C.
      • Mazoyer J.
      • Maillart E.
      • et al.
      Multiple sclerosis: is there a risk of worsening after yellow fever vaccination?.
      ).” Additionally, the time to first relapse did not differ between the two groups (
      • Papeix C.
      • Mazoyer J.
      • Maillart E.
      • et al.
      Multiple sclerosis: is there a risk of worsening after yellow fever vaccination?.
      ). Importantly, all related studies have relatively limited sample sizes.
      The utility of the YFV vaccine in the setting of individuals with MS on DMTs has also been an area of recent study. A 2018 study found that recurrent MS relapses were associated with the YFV vaccine when given within 2 months of fingolimod withdrawal (
      • Barnett E.D.
      Yellow fever: epidemiology and prevention.
      ). Study researchers extrapolate that in the setting of fingolimod withdrawal, MS can be potentially triggered by live-attenuated vaccines, such as the YFV vaccine (
      • Barnett E.D.
      Yellow fever: epidemiology and prevention.
      ). A later 2019 case study found a similar triggering effect of the YFV vaccine in the setting of fingolimod withdrawal (
      • Rolfes L.
      • Pawlitzki M.
      • Pfeuffer S.
      • et al.
      Fulminant MS reactivation following combined fingolimod cessation and yellow fever vaccination.
      ).
      Current guidelines per the French MS society articulate that live-attenuated vaccines are relatively contraindicated in patients recently treated with immunosuppressive drugs (
      • Reyes S.
      • Ramsay M.
      • Ladhani S.
      • et al.
      Protecting people with multiple sclerosis through vaccination.
      ). Individuals with MS and their healthcare providers must therefore consider the possible risk of an MS exacerbation following YFV vaccine administration as well as the risk of contracting the YFV (
      • Huttner A.
      • Eperon G.
      • Lascano A.M.
      • et al.
      Risk of MS relapse after yellow fever vaccination: a self-controlled case series.
      ). Altogether, further research is needed to ascertain any causal association between the YFV and MS exacerbations.

      10. Conclusion

      Vaccination of patients living with MS remains an indispensable tool to prevent future infections, minimize risk of relapse, and above all, maintain the health of this exceedingly vulnerable population. There is only a growing body of evidence that supports the safety, immunogenicity, and efficacy of this preventive health measure. According to the most recent studies discussed above, a majority of MS patients will likely benefit from vaccination against COVID-19, influenza, HBV, MMR, HPV, Streptococcus pneumoniae, and YFV while those treated with DMTs may need to carefully weigh the risks and benefits of pursuing or forgoing vaccination. Without a doubt, future studies will be instrumental in shaping current guidelines and recommendations. Of the studies reviewed in this article, several were limited by restricted sample sizes and homogenous patient groups. As such, further research will likely be needed to confirm their respective findings in broader, more diverse patient populations and explore novel strategies through which the health of MS patients can be more effectively safeguarded.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of Interest

      The authors have no conflicts of interest to disclose.

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