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Effects of MS disease-modifying therapies on responses to vaccinations: A review.

Published:August 01, 2020DOI:https://doi.org/10.1016/j.msard.2020.102439

      Abstract

      Background

      : Development of long-term immunologic memory relies upon humoral and cellular immune responses. Vaccinations aim to stimulate these responses against pathogens. Several studies have evaluated the impact of multiple sclerosis disease-modifying therapies on immune response to vaccines. Findings from these studies have important implications for people with multiple sclerosis who require vaccination and are using disease-modifying therapies.

      Methods

      : Searches using PubMed and other engines were conducted in May 2020 to collect studies evaluating the impact of various disease-modifying therapies on immune responses to vaccination.

      Results

      : Several studies demonstrated preserved immune responses in people treated with beta-interferons to multiple vaccine types. Limited data suggest vaccine responses to be preserved with dimethyl fumarate treatment, as well. Vaccine responses were reduced to varying degrees in those treated with glatiramer acetate, teriflunomide, sphingosine-1-phosphate receptor modulators, and natalizumab. The timing of vaccination played an important role in those treated with alemtuzumab. Humoral vaccine responses were significantly impaired by B cell depleting anti-CD20 monoclonal antibody therapies, particularly to a neoantigen. Data are lacking on vaccine responses in patients with multiple sclerosis taking cladribine and high-dose corticosteroids. Notably, the majority of these studies have focused on humoral responses, with few examining cellular immune responses to vaccination.

      Conclusions

      : Prior investigations into the effects of individual disease-modifying therapies on immune responses to existing vaccines can serve as a guide to expected responses to a SARS-CoV-2 vaccine. Responses to any vaccination depend on the vaccine type, the type of response (recall versus response to a novel antigen), and the impact of the individual disease-modifying therapy on humoral and cellular immunity in response to that vaccine type. When considering a given therapy, clinicians should weigh its efficacy against MS for the individual patient versus potential impact on responses to vaccinations that may be needed in the future.

      Keywords

      1. Introduction

      Multiple sclerosis (MS) is an immune-mediated demyelinating central nervous system (CNS) condition characterized by attacks of neurologic symptoms disseminated in space and time that often leads to disability. MS affects over 600,000 people in the United States with enormous costs to society. (
      • Wallin M.T.
      • Culpepper W.J.
      • Campbell J.D.
      • et al.
      The prevalence of MS in the United States: a population-based estimate using health claims data.
      ) MS disease-modifying therapies (DMTs) act on the immune system, by modulation or suppression. This review assesses the current evidence regarding the impact of MS DMTs on immune responses to existing vaccinations, highlighting implications for response to a potential vaccine against SARS-CoV-2.
      An effective immune response that provides long-term immunologic memory is driven primarily by the adaptive immune system, consisting of B cells (responsible for humoral, or antibody-mediated, immunity) and T cells (responsible for cell-mediated immunity). When stimulated in the presence of their target antigen, B and T cells clonally expand, with some transforming into memory cells, able to rapidly proliferate and become effector cells upon re-exposure to their target antigen. Upon activation, B cells can also differentiate into plasma cells that generate initially IgM and then IgG antibodies specific to the antigen. (

      Clem A.S.Fundamentals of vaccine immunology. In: J. Glob. Infect. Dis.. Vol 3.; 2011:73–78. doi:10.4103/0974-777X.77299.

      ) Table 1 summarizes vaccine types and how the immune responses they generate differ.
      Table 1Types of vaccines.
      Vaccine typeExamplesMechanism to generate immune responseAdvantagesDisadvantages
      InactivatedInfluenza (IM)
      Influenza vaccines typically include 2 influenza A antigens and one influenza B antigen per season.
      ,
      2009 influenza vaccine contained new H1N1 influenza A strain that had led to "swine flu" pandemic.
      , polio (IM)
      Uses entire pathogen that has been killed with chemicals, heat, or radiationStable and safe (no live virus present)Induces a weaker immune response, generally requires an adjuvant or additional booster doses
      Live attenuatedMMR, varicella, influenza (nasal), polio (PO), yellow feverUses entire pathogen that has been weakened in the laboratoryInduces strong humoral and cellular responses, conferring long-term immunity with one or two dosesGenerally contraindicated in those with weakened immune systems due to risk of generating disease
      Subunit – polysaccharide
      Unlikely to be used for SARS-CoV-2 vaccine.
      PPSV23Uses the most immunogenic components of the pathogenStable and safe (no live virus present)Expensive, must determine which combination of antigens will generate an effective immune response
      Subunit – proteinHBV, HPV
      Conjugate
      Unlikely to be used for SARS-CoV-2 vaccine.
      HiB, PCV13, MCV4Uses a protein antigen attached to a polysaccharide coating from the pathogenInduces a more effective immune response than use of polysaccharide antigen alone
      Toxoid
      Unlikely to be used for SARS-CoV-2 vaccine.
      Tetanus, diphtheriaUses inactivated bacterial toxinsStable and safe (no live bacteria present)Not highly immunogenic
      Nucleic acidN/AUses RNA or DNA encoding for the target antigen for antigen productionInexpensive and stableNot highly immunogenic, limited to protein antigens
      Recombinant vectorN/AUses a viral vector to introduce genetic material to cellsMore specific delivery of genes to target cellsMay induce neutralizing antibodies, limiting their effect
      Abbreviations: Hemophilus influenzae type B (HiB); Hepatitis B virus (HBV); human papilloma virus (HPV); intramuscular (IM); measles/mumps/rubella (MMR); oral (PO); quadrivalent meningococcal conjugate (MCV4); 13-valent pneumococcal conjugate (PCV13); 23-valent pneumococcal polysaccharide (PPSV23).
      a Influenza vaccines typically include 2 influenza A antigens and one influenza B antigen per season.
      b 2009 influenza vaccine contained new H1N1 influenza A strain that had led to "swine flu" pandemic.
      c Unlikely to be used for SARS-CoV-2 vaccine.
      Humoral responses to vaccines are generally measured using titers of IgG antibodies against the particular antigen, though use of the hemagglutination inhibition (HI) assay is an exception. (
      • Ayling K.
      • Vedhara K.
      • Fairclough L
      Measuring vaccine responses in the multiplex era..
      ) The HI assay reports the inverse of the dilution (the titer) at which a patient's antibody-containing serum is no longer able to inhibit the viral hemagglutination property. For inactivated influenza vaccine, an HI titer of ≥40 is considered protective. (
      • Zacour M.
      • Ward B.J.
      • Brewer A.
      • et al.
      Standardization of Hemagglutination Inhibition Assay for Influenza Serology Allows for High Reproducibility between Laboratories.
      ) Cellular immune responses to vaccines are less well-studied, and measurement methods are highly variable. Irrespective of vaccine type, immune responses to vaccination are generally more robust in women, in whom MS has a predilection. (
      • Flanagan K.L.
      • Fink A.L.
      • Plebanski M.
      • Klein S.L
      Sex and Gender Differences in the Outcomes of Vaccination over the Life Course.
      )
      Vaccine safety in MS was a subject of debate throughout the 1990s and 2000s, as seasonal influenza, measles/mumps/rubella (MMR), Hepatitis B (HBV), H1N1 influenza, and human papillomavirus (HPV) vaccines were all implicated and subsequently refuted as being linked to MS development or worsening. (
      • Mailand M.T.
      • Frederiksen J.L
      Vaccines and multiple sclerosis: a systematic review.
      ;
      • Stratton K.
      • Ford A.
      • Rusch E.
      • Clayton E.W
      Adverse Effects of Vaccines: Evidence and Causality.
      ;
      • Moriabadi N.F.
      • Niewiesk S.
      • Kruse N.
      • et al.
      Influenza vaccination in MS: absence of T-cell response against white matter proteins.
      ;
      • Miller A.E.
      • Morgante L.A.
      • Buchwald L.Y.
      • et al.
      A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis.
      ;
      • 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.
      ;
      • Auriel E.
      • Gadoth A.
      • Regev K.
      • Karni A
      Seasonal and H1N1v influenza vaccines in MS: safety and compliance.
      ;
      • Confavreux C.
      • Suissa S.
      • Saddier P.
      • Bourdes V.
      • Vukusic S
      Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group.
      ;
      • Langer-Gould A.
      • Qian L.
      • Tartof S.Y.
      • et al.
      Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases.
      ) Vaccine efficacy in MS has been less controversial, as studies of untreated MS patients have not shown differences in responses compared to healthy controls (HC). (
      • Moriabadi N.F.
      • Niewiesk S.
      • Kruse N.
      • et al.
      Influenza vaccination in MS: absence of T-cell response against white matter proteins.
      ) Regulatory bodies now recommend vaccinating people with MS on a normal schedule, with some caveats regarding live attenuated vaccines. (

      ACIP Altered Immunocompetence Guidelines for Immunizations | Recommendations | CDC. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html#t-01.

      ;
      • Lebrun C.
      • Vukusic S
      Immunization and multiple sclerosis: recommendations from the French multiple sclerosis society.
      ;
      • Epstein D.J.
      • Dunn J.
      • Deresinski S
      Infectious Complications of Multiple Sclerosis Therapies: implications for Screening, Prophylaxis, and Management.
      )
      The various immunomodulatory and immunosuppressive effects of different DMTs add complexity regarding vaccinations. Live vaccines are generally contraindicated in MS patients on immunosuppressive treatments. Mechanistically, DMTs that impact the adaptive immune system may decrease the efficacy of vaccines by impairing the development of long-term memory. (
      • Loebermann M.
      • Winkelmann A.
      • Hartung H.P.
      • Hengel H.
      • Reisinger E.C.
      • Zettl U.K
      Vaccination against infection in patients with multiple sclerosis.
      ) This review evaluates the current evidence regarding the impact of DMTs for MS on vaccine responses in humans.

      2. Methods

      A PubMed search was performed on May 1, 2020 for English language articles that were published between January 1, 1995 and May 1, 2020 using the MeSH terms multiple sclerosis and vaccine with each individual DMT. Articles not focusing on vaccine response in the setting of DMT use, such as basic pathophysiologic reviews, author commentaries, reports of vaccines used as MS therapy, and animal studies were excluded. Additional references were obtained from a Google search of each individual DMT and immunization and vaccination (May 2–3, 2020), secondary review of the articles discovered in these searches, searches of ClinicalTrials.gov (May 1, 2020) and CDC.gov (May 3, 2020), and review of manufacturer prescribing information for each DMT. Bias was qualitatively assessed for each study and funding sources are noted in Table 2. Levels of evidence for each study are assigned based on the Oxford centre for Evidence-Based Medicine 2011 Levels of Evidence. ()
      Table 2Studies of MS DMT effects on immune responses to vaccinations.
      DMTMechanism of actionType of studyPatient descriptionControl groupIntervention(s)Outcome measure(s)Result(s)SupportLevel of EvidenceCitationSummary
      Beta-interferonsInhibition of T cell activation and proliferation; apoptosis of autoreactive T cells; induction of regulatory T cells; inhibition of leukocyte migration across BBB; cytokine modulationProspective, non-randomized, open label study86 relapsing MS patients taking IFN beta77 untreated MS patientsInactivated seasonal influenza vaccineHI titer ≥ 40No significant difference in proportion reaching HI titer ≥ 40Industry supportedLevel 3(
      • Schwid S.R.
      • Decker M.D.
      • Lopez-Bresnahan M
      Immune response to influenza vaccine is maintained in patients with multiple sclerosis receiving interferon beta-1a.
      )
      Vaccine responses were not adversely affected by beta-interferon treatment.
      Non-randomized, open label, parallel group observational study128 relapsing MS patients taking IFN beta (n = 46), teriflunomide 7 mg/day (n = 41), teriflunomide 14 mg/day (n = 41)NoneInactivated seasonal influenza vaccineHI titer ≥ 40Lower (but non-significant) rates of HI titers ≥ 40 for one influenza antigen in teriflunomide 14 mg/day group Lower post/pre vaccination GMT ratio in both teriflunomide dose groupsIndustry supportedLevel 3(
      • Bar-Or A.
      • Freedman M.S.
      • Kremenchutzky M.
      • et al.
      Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis.
      )
      Prospective observational open-label study26 relapsing MS patients taking IFN beta33 healthy controlsInactivated seasonal influenza vaccineAnti-influenza IgM/IgG pre- and post-vaccination (measured by ELISA)No significant difference in vaccine-induced humoral immune responsesInvestigator initiated, industry supportedLevel 3(
      • Mehling M.
      • Fritz S.
      • Hafner P.
      • et al.
      Preserved antigen-specific immune response in patients with multiple sclerosis responding to IFNβ-therapy.
      )
      Retrospective, non-randomized, observational studyH1N1 analysis: RRMS patients taking IFN beta (n = 36), GA (n = 37), natalizumab (n = 17), mitoxantrone (n = 11) Seasonal influenza analysis: RRMS patients taking IFN beta (n = 17), GA (n = 12), natalizumab (n = 8), mitoxantrone (n = 4)H1N1 analysis: 216 healthy controls Seasonal influenza analysis: 73 healthy controlsInactivated H1N1 influenza vaccine Inactivated seasonal influenza vaccineHI titer ≥ 40H1N1 analysis: Similar proportion reaching HI titer ≥ 40 of IFN beta and healthy controls, but reduced proportion in GA, natalizumab, and mitoxantrone groups Seasonal influenza analysis: Higher proportion reaching HI titer ≥ 40 against multiple influenza A strains in IFN beta group compared to GA, natalizumab, and mitoxantrone groupsNo industry supportLevel 3(
      • 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.
      )
      Prospective observational studyMainly RRMS patients taking IFN beta-1a/1b (n = 25), GA (n = 23), fingolimod (n = 15), natalizumab (n = 12); untreated (n = 12)62 healthy controlsInactivated seasonal influenza vaccineHI titer ≥ 40No significant difference in proportion reaching HI titer ≥ 40 between IFN beta, GA, and untreated MS patients compared to HC; reduced rates in fingolimod and natalizumab groupsNo industry supportLevel 3(
      • 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.
      )
      Open-label non-randomized study71 RRMS patients taking IFN beta (n = 33) and DMF (n = 38)NoneTetanus-diphtheria toxoid vaccine 23-valent pneumococcal polysaccharide vaccine Meningococcal conjugate vaccineProportion with ≥ 2-fold rise in antigen-specific IgG levels after vaccinationNo difference between IFN beta and DMF groups in proportion with ≥ 2-fold rise in IgG levels for any vaccine typesIndustry supportedLevel 3(
      • Von Hehn C.
      • Howard J.
      • Liu S.
      • et al.
      Immune response to vaccines is maintained in patients treated with dimethyl fumarate.
      )
      Prospective, multicenter, non-randomized, observational studyMS patients (92.2% RRMS) taking beta IFN (n = 45), GA (n = 26), fingolimod (n = 6), natalizumab (n = 14)None (various DMT arms compared to each other)Inactivated seasonal influenza vaccineHI titer ≥ 40 or 4-fold rise in post-vaccination HI titerSignificant difference amongst various DMT arms protected against one A strain and protected against all strains, with higher rates of protection in IFN beta (highest) and GA groups compared to fingolimod and natalizumab groupsIndustry supportedLevel 3(
      • 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.
      )
      Glatiramer acetateBinds HLA class II; induction of anti-inflammatory T cell responses and alterations in T cell functionSee above under Beta-interferonsLevel 3(
      • 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.
      )
      Responses to the inactivated influenza vaccine were reduced compared to healthy controls. Responses to live attenuated and subunit vaccines have not been reported for in this population.
      See above under Beta-interferonsLevel 3(
      • 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.
      )
      See above under Beta-interferonsLevel 3(
      • 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.
      )
      TeriflunomideInhibition of de novo pyrimidine synthesis, preventing expansion of autoreactive lymphocytes (but preserving memory cells)See above under Beta-interferonsLevel 3(
      • Bar-Or A.
      • Freedman M.S.
      • Kremenchutzky M.
      • et al.
      Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis.
      )
      Responses to multiple vaccine types probably were sufficient, if somewhat blunted.
      Prospective, randomized, double-blind, parallel-group study23 healthy people taking teriflunomide 14 mg/day23 healthy people taking placeboInactivated rabies vaccine (to assess neoantigen response) Candida, Trichophyton, tuberculin (to assess DTH)Anti-rabies antibody titers Proportion with positive DTH reactionSignificantly lower GMTs at Days 31 and 38 in teriflunomide group, but all patients reached seroprotective levels No difference in DTH responses between groupsIndustry supportedLevel 2(
      • Bar-Or A.
      • Wiendl H.
      • Miller B.
      • et al.
      Randomized study of teriflunomide effects on immune responses to neoantigen and recall antigens.
      )
      FumaratesEnhancement of Nrf2 transcriptional pathway, decreases downstream oxidative stress, inhibits NfκB pathwaySee above under Beta-interferonsLevel 3(
      • Von Hehn C.
      • Howard J.
      • Liu S.
      • et al.
      Immune response to vaccines is maintained in patients treated with dimethyl fumarate.
      )
      Toxoid and polysaccharide/conjugate vaccine responses were not significantly affected, though only one study had evaluated this.
      S1P receptor modulatorsInhibition of S1P receptor to inhibit lymphocyte migration (lymphocytes remain sequestered in lymph nodes)Open-label, observational, prospective study14 MS patients taking fingolimod18 healthy controlsInactivated seasonal influenza vaccineAnti-influenza IgM/IgG Post-vaccination frequency of γ-interferon cells with re-exposureNo significant difference in humoral or cellular responsesIndustry supportedLevel 4(
      • Mehling M.
      • Hilbert P.
      • Fritz S.
      • et al.
      Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients.
      )
      Responses to inactivated and toxoid vaccines were diminished in those taking fingolimod at the time of vaccination. Responses to the inactivated influenza vaccine were diminished in those taking siponimod at the time of vaccination.
      Randomized, blinded, placebo-controlled study95 relapsing MS patients taking fingolimod43 relapsing MS patients taking placeboInactivated seasonal influenza vaccine Tetanus toxoid boosterProportion with seroprotective HI or anti-TT titers or 4-fold increase in HI or anti-TT titerSignificantly lower response rates in fingolimod group at multiple timepoints to influenza and TT vaccinesIndustry supportedLevel 2(
      • Kappos L.
      • Mehling M.
      • Arroyo R.
      • et al.
      Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis.
      )
      See above under Beta-interferonsLevel 3(
      • 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.
      )
      See above under Beta-interferonsLevel 4(
      • 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.
      )
      Randomized, prospective, placebo-controlled study90 healthy people taking siponimod (n = 30 stopped 7 days prior to vaccination; n = 30 took concomitantly; n = 30 stopped 10 days prior to vaccination and restarted 14 days after vaccination)30 healthy people taking placeboInactivated seasonal influenza vaccine 23-valent pneumococcal polysaccharide vaccineHI titer ≥ 40; post-vaccination increase in GMT ≥ 2.5-fold from baseline; proportion with ≥ 4-fold increase from baseline ≥ 2-fold increase in anti-pneumococcal IgG titerSimilar responses between groups to influenza A strains, but lower seroprotective response rate and GMTs in interrupted and concomitant siponimod groups for multiple influenza strains High response rates in all groups to PPSV23Industry supportedLevel 2(
      • Ufer M.
      • Shakeri-Nejad K.
      • Gardin A.
      • et al.
      Impact of siponimod on vaccination response in a randomized, placebo-controlled study.
      )
      NatalizumabMonoclonal antibody against α4-integrins, causing inhibition of lymphocyte migration across BBBProspective, observational, non-randomized study17 RRMS patients taking natalizumab10 healthy controlsInactivated seasonal influenza vaccineProportion with ≥ 50% increase in anti-influenza IgG from baselineNo significant difference in anti-influenza IgG changes, with non-significant trend to lower titers in natalizumab groupIndustry supportedLevel 3(
      • Vågberg M.
      • Kumlin U.
      • Svenningsson A
      Humoral immune response to influenza vaccine in natalizumab-treated MS patients.
      )
      Inadequate vaccine responses occurred in some patients taking natalizumab.
      Randomized, open-label, prospective, controlled study30 relapsing MS patients taking natalizumab30 relapsing MS patients delaying initiation of natalizumab until 2 months post-vaccinationTetanus toxoid KLH neoantigenProportion with ≥ 50% increase in antigen-specific IgG from baselineNo significant differences in antigen-specific IgG response rates, with non-significant trend to lower titers in natalizumab groupIndustry supportedLevel 3(
      • Kaufman M.
      • Pardo G.
      • Rossman H.
      • Sweetser M.T.
      • Forrestal F.
      • Duda P
      Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis.
      )
      See above under Beta-interferonsLevel 3(
      • 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.
      )
      See above under Beta-interferonsLevel 3(
      • 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.
      )
      See above under Beta-interferonsLevel 3(
      • 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.
      )
      B cell depleting therapiesMonoclonal antibodies against CD20, which depletes circulating B cellsRandomized, open-label, prospective study68 relapsing MS patients who received one dose of ocrelizumab 600 mg34 relapsing MS patients, untreated or taking beta IFNTetanus toxoid KLH neoantigen 23-valent pneumococcal polysaccharide vaccine4-fold increase in antigen-specific IgG from baseline or development of protective antibody levelsSignificantly lower response rates in ocrelizumab group to TT, KLH, and PPSV23, and lower responses to PCV13 booster vaccine and seasonal influenza vaccineIndustry supportedLevel 2(
      • Stokmaier D.
      • Winthrop K.
      • Chognot C.
      • et al.
      Effect of Ocrelizumab on Vaccine Responses in Patients With Multiple Sclerosis (S36.002).
      )
      Vaccine responses, especially to neoantigens and T cell-independent antigens, were significantly impaired by B cell depletion.
      Randomized, prospective study69 rheumatoid arthritis patients taking rituximab (1000 mg twice, given 2 weeks apart) plus methotrexate34 rheumatoid arthritis patients taking methotrexate aloneTetanus toxoid KLH neoantigen 23-valent pneumococcal polysaccharide vaccine Candida (to assess DTH)Proportion with ≥ 4-fold increase in antigen-specific IgG from baselineSimilar responses between groups to TT and DTH to Candida, but significantly reduced responses to PPSV23 and KLH in RTX/MTX group compared with MTX aloneIndustry supportedLevel 2(
      • Bingham C.O.
      • Looney R.J.
      • Deodhar A.
      • et al.
      Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial.
      )
      AlemtuzumabMonoclonal antibody against CD52, which depletes circulating autoreactive T and B cellsProspective case-control study24 RRMS patients taking alemtuzumabNoneTetanus-diphtheria toxoid vaccine Inactivated poliomyelitis vaccine Hemophilus influenzae type b conjugate vaccine Quadrivalent meningococcal vaccine 23-valent pneumococcal polysaccharide vaccine4-fold increase in antigen-specific IgG from baseline or development of protective antibody levelsSimilar responses to all vaccine types in study patients compared with historical controls, though proportion responding to vaccination within 6 months after treatment was lowerNo industry supportLevel 3(
      • McCarthy C.L.
      • Tuohy O.
      • Compston D.A.S.
      • Kumararatne D.S.
      • Coles A.J.
      • Jones J.L
      Immune competence after alemtuzumab treatment of multiple sclerosis.
      )
      Responses to multiple vaccine types were maintained in patients taking alemtuzumab in the one available study, though somewhat blunted for vaccinations within 6 months of dosing.
      Abbreviations: blood-brain barrier (BBB); delayed-type hypersensitivity (DTH); dimethyl fumarate (DMF); disease-modifying therapy (DMT); enzyme-linked immunosorbent assay (ELISA); geometric mean titer (GMT); glatiramer acetate (GA); healthy controls (HC); hemagglutination inhibition (HI); human leukocyte antigen (HLA); immunoglobulin G (IgG); immunoglobulin M (IgM); interferon (IFN); keyhole limpet hemocyanin (KLH); methotrexate (MTX); multiple sclerosis (MS); nuclear factor erythroid 2-related factor 2 (Nrf2); nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB); 13-valent pneumococcal conjugate vaccine (PCV13); 23-valent pneumococcal polysaccharide vaccine (PPSV23); relapsing-remitting multiple sclerosis (RRMS); rituximab (RTX); sphingosine-1-phosphate (S1P); tetanus toxoid (TT).

      3. Discussion

      Table 2 provides a summary of all published studies of vaccine responses in people using FDA-approved DMTs for MS.

      3.1 Beta-interferon effects on responses to vaccines

      A prospective, non-randomized, open label study compared responses to an inactivated influenza vaccine in 86 relapsing MS patients taking interferon beta-1a 44 mcg three times weekly and 77 untreated relapsing MS patients. (
      • Schwid S.R.
      • Decker M.D.
      • Lopez-Bresnahan M
      Immune response to influenza vaccine is maintained in patients with multiple sclerosis receiving interferon beta-1a.
      ) There was no difference in the proportion of patients in each group with seroprotective HI titers (93.0% beta-interferon group vs. 90.9% untreated group), or the proportions mounting 2-fold (75.6% vs. 75.3%) and 4-fold (50.0% vs. 58.4%) increase in HI titers. This study offers Level 3 evidence that MS patients taking high-dose, high-frequency beta-interferon mount an appropriate immune response to the influenza vaccine.
      Another study compared immune responses after seasonal influenza vaccination in 82 teriflunomide-treated relapsing MS patients to 46 beta-interferon-treated relapsing MS patients. (
      • Bar-Or A.
      • Freedman M.S.
      • Kremenchutzky M.
      • et al.
      Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis.
      ) For all 3 influenza strains used, >90% of those in the beta-interferon group had protective HI titers 28 days post-vaccination. Ratios of post-vaccination to pre-vaccination geometric mean titers (GMT) were all ≥3.4, indicating an effective immune response. This study was limited by lack of an untreated MS control group. Level 3 evidence.
      A prospective observational study evaluated the effects of the inactivated influenza vaccine in 26 patients taking a variety of beta-interferon preparations, comparing anti-influenza IgM and IgG titers to those in 33 HC at multiple time-points post-vaccination. (
      • Mehling M.
      • Fritz S.
      • Hafner P.
      • et al.
      Preserved antigen-specific immune response in patients with multiple sclerosis responding to IFNβ-therapy.
      ) No significant difference between groups was found in the degree or duration of these humoral immune responses, with the exception of a significantly higher anti-influenza B IgG titer at days 14 and 28 in the beta-interferon group. Cellular immune responses were also compared by measuring the frequency of T cells secreting gamma-interferon in response to influenza antigen, with no differences between groups. Level 3 evidence.
      A retrospective, non-randomized, observational study evaluated responses to the vaccine against 2009 H1N1 influenza (a neoantigen responsible for the “swine flu” pandemic) and the 2010 seasonal influenza vaccine in MS patients on a variety of DMTs. (
      • 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.
      ) The beta-interferon group (n = 36 for 2009 and n = 17 for 2010) showed no significant differences from HC in the proportion reaching a protective HI titer in response to either the 2009 H1N1 vaccine (44.4% vs. 43.5%) or the 2010 seasonal influenza vaccine (88.2% vs. 71.2% [H1N1 influenza A strain] and 88.2% vs. 79.5% [H3N2 influenza A strain]). Protective antibody titers were measured several months post-vaccination, demonstrating durability. Study limitations include the small numbers of patients in each DMT subgroup and the use of questionnaires that may have led to recall bias. Level 3 evidence.
      The same investigator group performed another observational study of 25 MS patients taking beta-interferons and compared influenza vaccine responses at multiple post-vaccination intervals to 62 HC. (
      • 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.
      ) No differences in the proportion reaching a protective HI titer were observed between the two groups at any time, including at the peak antibody response time of 3 months (88.0% in the beta-interferon group vs. 94.6% in HC). Level 3 evidence.
      Another observational study evaluating vaccine responses in 38 patients taking dimethyl fumarate included an arm of 33 relapsing-remitting MS (RRMS) patients taking beta-interferons. (
      • Von Hehn C.
      • Howard J.
      • Liu S.
      • et al.
      Immune response to vaccines is maintained in patients treated with dimethyl fumarate.
      ) IgG titers were assessed pre- and post-vaccination with 3 vaccines to assess different types of immune responses: tetanus-diphtheria toxoid vaccine to assess T-cell dependent anamnestic humoral response, 23-valent pneumococcal polysaccharide vaccine (PPSV23) to assess T-cell independent humoral response, and quadrivalent meningococcal conjugate vaccine (MCV4) to assess neoantigen responses. Those with a ≥ 2-fold rise in IgG levels after vaccination were considered responders. For anti-tetanus/diphtheria, there was no difference in the responder proportion (dimethyl fumarate group 68% vs. beta-interferon group 73%). Pneumococcal vaccination responses were not significantly different between the two groups, though there was considerable variability in GMT ratios across serotypes. Neoantigen responses to MCV4 were not different, with 53% of each group demonstrating a 2-fold rise in IgG. Post- to pre-vaccination GMT ratios were similar in the dimethyl fumarate and beta-interferon groups (4.1 vs 4.3, respectively). Level 3 evidence.
      A prospective, multicenter, non-randomized study evaluated influenza vaccine responses in patients treated with a variety of DMTs. (
      • 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.
      ) Patients taking beta-interferons showed a significantly greater proportional vaccine response as measured by HI titer than other DMT groups taking glatiramer acetate, fingolimod, and natalizumab. Beta-interferon-treated patients reached seroprotective rates of >80% for each strain, and reached protective HI titers to all 3 strains (73.3% of 45 patients) more frequently than those treated with glatiramer acetate (57.7% of 26 patients), fingolimod (33.3% of 6 patients), and natalizumab (14.3% of 14 patients). This study was limited by lack of an untreated control group and low numbers, especially in the fingolimod and natalizumab groups. Level 3 evidence.
      Together, these studies convincingly demonstrate adequate immune responses to a variety of vaccine mechanisms in MS patients treated with beta-interferons.

      3.2 Glatiramer acetate effects on responses to vaccines

      Some of the already-discussed studies of vaccine immune responses in people receiving beta-interferons also included people receiving glatiramer acetate. In the observational study of immune responses to the 2009 H1N1 pandemic influenza vaccine and the 2010 seasonal influenza vaccine discussed above, (
      • 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.
      ) 37 MS patients taking glatiramer acetate had substantially lower rates of protection post-vaccination with the 2009 H1N1 “swine flu” vaccine (21.6%; GMT 153) compared to 216 HC (43.5%; GMT 170). Reduced rates of seroprotection were also observed for two different antigens in the 2010 seasonal influenza vaccine (58.3% and 41.7% in the 12 patients in the glatiramer acetate group vs. 71.2% and 79.5% in 73 HC). Level 3 evidence.
      In a follow-up study of immune responses to the 2012/2013 seasonal influenza vaccine, (
      • 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.
      ) most of the 23 MS patients treated with glatiramer acetate responded to the H1N1 influenza antigen (91.3% seroprotection at 3 months), similar to the 56 HC (94.6%), 14 untreated MS patients (92.9%), and 25 beta-interferon treated patients (88.0%). Responses to the H3N2 influenza antigen were low for all groups. Although the glatiramer acetate group responded less well than the beta-interferon and HC groups, this difference was not significant. Level 3 evidence.
      In the 2019 prospective, multicenter, non-randomized study of several different DMTs discussed above, (
      • 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.
      ) 26 patients taking glatiramer acetate were included. The glatiramer acetate group demonstrated post-vaccination seroprotection rates to the 3 influenza antigens of 88.5%, 73.1%, and 80.8%, close to rates of the 45 people in the beta-interferon group (84.4%, 91.1%, and 88.9%). Level 3 evidence.
      Although immune responses to influenza vaccines were observed in glatiramer acetate-treated patients in these studies, the results suggest that responses were reduced compared to HC and to those treated with beta-interferons. These studies regarding inactivated vaccination responses may not be generalizable to other vaccine types (such as live attenuated, nucleic acid, recombinant vector, or subunit vaccines), for which immune responses have not been reported in people on glatiramer acetate.

      3.3 Teriflunomide effects on responses to vaccines

      A study already mentioned in the beta-interferon section investigated the effect of teriflunomide on influenza vaccination responses in MS patients. (
      • Bar-Or A.
      • Freedman M.S.
      • Kremenchutzky M.
      • et al.
      Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis.
      ) This non-blinded, nonrandomized, multicenter, multinational, parallel-group study included 128 patients in 3 groups: teriflunomide 7 mg (n = 41), teriflunomide 14 mg daily (n = 41), and beta-interferons (n = 46, the reference population). More than 90% of all patients in all groups achieved seroprotection (HI titer ≥ 40) for the H1N1 and influenza B antigens. Seroprotection was lower in the H3N2 teriflunomide 14 mg group (76.9%), compared to 90% in the 7 mg per day teriflunomide and beta-interferon groups. GMT ratios were reduced in the teriflunomide groups (2.3–3.1) compared to the beta-interferon group (3.4–4.7). A limitation of this study is that it was not powered for comparisons of immune responses in the teriflunomide and beta-interferon groups. Level 3 evidence.
      A prospective, randomized, double-blind, parallel-group, placebo-controlled study compared antibody responses to rabies vaccine (neoantigen) and delayed type hypersensitivity (recall) to Candida albicans, Trichophyton, and tuberculin in 23 healthy people assigned to 14 mg/day teriflunomide with 23 healthy individuals assigned to placebo. (
      • Bar-Or A.
      • Wiendl H.
      • Miller B.
      • et al.
      Randomized study of teriflunomide effects on immune responses to neoantigen and recall antigens.
      ) GMTs for rabies antibodies were lower with teriflunomide than with placebo, but all subjects assigned to teriflunomide achieved seroprotective antibody levels. Teriflunomide had no adverse impact on the cellular memory response to recall antigens. Level 2 evidence.
      Overall, these studies indicate modest negative effects of teriflunomide 14 mg/day on immune response to influenza and rabies vaccinations.

      3.4 Effects of fumarates (dimethyl fumarate, diroximel fumarate) on responses to vaccines

      3.4.1 Dimethyl fumarate

      A single open-label, multicenter, non-randomized study evaluated the effects of dimethyl fumarate treatment on vaccination responses. (
      • Von Hehn C.
      • Howard J.
      • Liu S.
      • et al.
      Immune response to vaccines is maintained in patients treated with dimethyl fumarate.
      ) 38 patients on dimethyl fumarate 240 mg twice daily were compared to 33 patients treated with beta-interferon after vaccination with 3 vaccines to assess different types of immune responses. This study is discussed in detail in the section on beta-interferons above and provided Level 3 evidence that dimethyl fumarate treatment did not reduce T-cell dependent and humoral immune responses.

      3.4.2 Diroximel fumarate

      No relevant studies were found.

      3.5 Effects of sphingosine-1-phosphate receptor modulators on vaccine responses

      3.5.1 Fingolimod

      A small prospective study of immune responses to the seasonal influenza vaccine was performed in 14 fingolimod-treated MS patients and 18 HC. (
      • Mehling M.
      • Hilbert P.
      • Fritz S.
      • et al.
      Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients.
      ) Influenza antigen-specific production of IgM and IgG, and the frequency of gamma-interferon secreting cells after immunization, were not significantly altered by fingolimod treatment compared to HC. However, the two groups were not well matched, with HC being younger (mean age 37, range 19–46) than the MS patients (mean age 44, range 31–60), and HC were 33% female compared with 57% female in the MS group. Level 4 evidence.
      A blinded, randomized, multicenter, placebo-controlled study of response to seasonal influenza vaccine and tetanus toxoid (TT) booster was performed in 138 relapsing MS patients on either fingolimod 0.5 mg/day (n = 95) or placebo (n = 43). (
      • Kappos L.
      • Mehling M.
      • Arroyo R.
      • et al.
      Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis.
      ) At 3 weeks post-vaccination, responder rates (proportion achieving seroprotective HI titers or a 4-fold increase in antibody titers against at least one influenza strain) for fingolimod vs. placebo, respectively, were 54% vs. 85%. At 6 weeks, responder rates were 43% vs. 75%. For TT, responder rates were 40% vs. 61% at 3 weeks and 38% vs. 49% at 6 weeks. Although many fingolimod-treated MS patients were able to mount protective immune responses, this study provided Level 2 evidence that response rates were reduced in patients on fingolimod compared with placebo-treated patients.
      Fifteen patients on fingolimod were among the 90 MS patients and 62 HC included in a prospective study to measure antibody responses to the 2012/2013 influenza A H1N1 and H3N2 vaccine viruses. (
      • 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.
      ) The fingolimod group developed reduced rates of seroprotection to H1N1 compared with controls or MS patients on beta-interferons and glatiramer acetate. At 3 months, 6 months, and 12 months, seroprotection rates were 71.4%, 58.3%, and 22.2% in the fingolimod group vs. 94.6%, 94%, and 70.4% in HC. The response to H3N2 was even poorer in those on fingolimod, with 21.4% protected at 3 months, 8.3% protected at 6 months, and 0% at 12 months post-vaccination compared with 69.6%, 58%, and 57.4% for HC. Level 3 evidence.
      A non-randomized, prospective, non-controlled study of MS patients who underwent seasonal influenza vaccination discussed in earlier sections of this review included 6 people on fingolimod. (
      • 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.
      ) A lower proportion of fingolimod‐treated patients achieved protection to H3N2 and influenza B compared to those on beta-interferons or glatiramer acetate. Interpretation of these results is limited by the very small size of the fingolimod subgroup. Level 4 evidence.
      Taken together, these studies indicate that concurrent fingolimod reduces immune response to influenza vaccinations.

      3.5.2 Siponimod

      Responses to seasonal influenza and PPSV23 vaccines were assessed in 120 healthy persons treated with siponimod 2 mg/day or placebo. (
      • Ufer M.
      • Shakeri-Nejad K.
      • Gardin A.
      • et al.
      Impact of siponimod on vaccination response in a randomized, placebo-controlled study.
      ) The randomized, prospective study enrolled 30 people per group into 3 siponimod treatment groups and a placebo group. Treatment groups were “preceding siponimod” (stopping 7 days prior to immunization), “concomitant” (non-interrupted siponimod), and “interrupted siponimod” (treatment interrupted 10 days prior to and for 14 days after immunization). The durations of stopping or interrupting siponimod were based on the known time of 7–10 days for circulating lymphocytes to return after drug discontinuation. Each person received seasonal influenza and PPSV23 vaccines, with blood samples obtained at baseline and multiple times after immunization. Seroprotection rate ≥70%, GMT increase of ≥2.5 vs. baseline, and IgG response rate of ≥40% were examined. At 28 days, each group exceeded the 70% response threshold and a GMT increase ≥2.5-fold for both influenza A antigens compared with baseline. For one of the two influenza B viruses, the seroprotection response threshold of ≥ 70% was not met for the interrupted and concomitant siponimod groups. Over 90% in each group responded to PPSV23 with >2-fold increase in IgG on day 28 vs. baseline. Compared to the placebo group, the proportions of people with titer increased ≥ 4-fold at day 28 were decreased in the concomitant and interrupted siponimod groups for H1N1, H3N2, and one of the influenza B viruses. GMTs over time were lower for the concomitant siponimod group for both influenza A strains and one of the influenza B strains compared to the other 3 groups. This study provides Level 2 evidence of a lower response to influenza vaccines in those on siponimod at time of vaccination. Stopping siponimod at least 7 days prior to administration of a vaccine and resuming siponimod (after up-titration) 2 or more weeks later is a potential strategy to improve vaccine response.

      3.5.3 Ozanimod

      No relevant studies were found.

      3.6 Oral cladribine effects on responses to vaccines

      No relevant studies have been reported in MS patients on oral cladribine. A vaccine study is being planned by the manufacturer.

      3.7 Natalizumab effects on responses to vaccines

      An early study of 17 natalizumab-treated MS patients (14 female) and 10 HC (5 female) examined antibody response to seasonal influenza vaccination. (
      • Vågberg M.
      • Kumlin U.
      • Svenningsson A
      Humoral immune response to influenza vaccine in natalizumab-treated MS patients.
      ) Mean antibody titers to influenza A and B were not different between the two groups, with a non-significant trend towards lower titers to influenza A for the natalizumab group. This study was likely underpowered, and the study groups were not well matched. Level 4 evidence.
      A randomized, controlled, open-label study of 60 people with relapsing MS was done to study the response to a recall antigen (TT) and the neoantigen Keyhole limpet hemocyanin (KLH). (
      • Kaufman M.
      • Pardo G.
      • Rossman H.
      • Sweetser M.T.
      • Forrestal F.
      • Duda P
      Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis.
      ) Patients were randomized 1:1 to control or natalizumab groups. The control group received immunizations shortly after randomization and delayed starting natalizumab until after day 56, whereas those randomized to natalizumab were treated with natalizumab beginning 6 months prior to immunizations. A lower proportion of those in the natalizumab group responded to TT and to KLH at day 56. Although the differences were not statistically significant, the study may have been underpowered. Level 3 evidence.
      A previously mentioned real-world study of 113 MS patients and 216 HC examined response to the 2009 H1N1 pandemic “swine flu” vaccine. (
      • 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.
      ) Seventeen of the MS patients in that study were on natalizumab. Only 4 of the 17 (23.5%) achieved seroprotective HI titers after immunization, compared to 94 of 216 controls (43.5%) and 16 of 36 (44.4%) of those on beta-interferon. Level 3 evidence.
      The same group of investigators performed a prospective study of responses to the seasonal influenza vaccination in 2012/2013 in 90 MS patients on four different immunomodulatory therapies and 62 HC at baseline and 3, 6, and 12 months post-immunization. (
      • 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.
      ) The proportion of those few patients on natalizumab (n = 11 at 3 months, n = 8 at 6 months, and n = 9 at 12 months) that had adequate response to the immunization was consistently 10% or more lower than HC and MS patients on beta-interferons. Level 3 evidence.
      In the previously-discussed 2019 non-randomized, prospective, study of 102 MS patients who underwent seasonal influenza vaccination, 14 were on natalizumab. (
      • 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.
      ) For H3N2 and the influenza B antigen, only 28.6% and 57.1%, respectively, of those on natalizumab achieved sufficient response, compared to 91.1% and 88.9% for the 45 people taking beta-interferon. Level 3 evidence.
      Overall, these studies provide evidence that an inadequate response to some immunizations occurs in a sizeable proportion of people being treated with natalizumab.

      3.8 Effects of anti-CD20 B cell depleting agents on responses to vaccines

      3.8.1 Ocrelizumab

      The VELOCE study (NCT02545868) investigated the effect of ocrelizumab treatment on responses to specific vaccine types. (
      • Stokmaier D.
      • Winthrop K.
      • Chognot C.
      • et al.
      Effect of Ocrelizumab on Vaccine Responses in Patients With Multiple Sclerosis (S36.002).
      ) Relapsing MS patients were randomized 2:1 into Group A (n = 68), receiving a single dose of ocrelizumab 600 mg; or Control Group B (n = 34), on no DMT or taking interferon-beta 1a 44 mcg three times weekly. T-cell–dependent recall response was assessed with TT booster, PPSV23 was used to examine a mainly B-cell–dependent response, and the 13-valent pneumococcal conjugate vaccine (PCV13) was used to evaluate the response to a booster of PPSV23. Response to the seasonal influenza vaccine tested response to an inactivated vaccine, and immunization with KLH tested the humoral response to a previously unknown antigen. The ocrelizumab group had a poorer humoral response to vaccinations. 23.9% of the ocrelizumab group vs. 54.5% of the control group had responded (4-fold increase in antigen-specific IgG from baseline or development of protective antibody levels) to TT booster at 8 weeks post-vaccination. Positive response to ≥5 serotypes in PPSV23 at 4 weeks was 71.6% in the ocrelizumab and 100% in the control group. The PCV13 booster did not enhance the response to 12 serotypes in common with PPSV23 in the ocrelizumab group, whereas it did for the control group. The humoral response to KLH was greatly decreased in the ocrelizumab group vs. the control group. After immunization with KLH, the GMTs for IgM and IgG for the control group were almost 2000 and 60,000, respectively, but were less than 500 for IgM and IgG in those treated with ocrelizumab. Seroprotective titers at 4 weeks against five influenza strains (season 2015/2016 and 2016/2017) ranged from 55.6% to 80.0% in the ocrelizumab group, compared to 75.0% to 97.0% in the control group. Level 2 evidence.

      3.8.2 Rituximab

      Responses to vaccination were studied in non-MS populations treated with the B cell depleting chimeric monoclonal antibody, rituximab. In one study of 103 rheumatoid arthritis patients, patients were randomized 2:1 to take rituximab 1000 mg IV twice two weeks apart in addition to methotrexate (10–25 mg po weekly) vs. methotrexate alone. Patients in each treatment group were examined for response to TT, PPSV23, and KLH, and for DTH to Candida albicans. (
      • Bingham C.O.
      • Looney R.J.
      • Deodhar A.
      • et al.
      Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial.
      ) Responses to TT vaccine were similar, with 39.1% of rituximab/methotrexate vs. 42.3% of methotrexate alone patients achieving a 4-fold or greater rise in titer. DTH responses to the C. albicans skin test were similarly positive in 77.4% of rituximab/methotrexate patients and 70% of those on methotrexate alone. However, rituximab/methotrexate patients had reduced response to PPSV23: 57% of patients had a 2-fold rise in titer in response to >1 serotype, compared with 82% of patients treated with methotrexate alone. Only 47% of patients on rituximab/methotrexate had detectable anti-KLH IgG, compared to 93% of those on methotrexate alone. Level 2 evidence.
      These two studies indicate that responses to neoantigens and T cell-independent antigens are greatly reduced by B cell depletion with anti-CD20 monoclonal antibody treatments. Recall responses to the T cell–dependent TT antigen and DTH responses were less affected by B cell depletion, with some differences noted in response to TT between the two studies which used different B-cell depleting agents. Both studies were done in the first year after B cell depletion; responses might change after longer treatment duration.

      3.9 Alemtuzumab effects on responses to vaccines

      Twenty-four people with MS taking alemtuzumab for median 18 months (range 1.5 to 86 months) took part in an investigation of the effects of alemtuzumab on vaccination responses. (
      • McCarthy C.L.
      • Tuohy O.
      • Compston D.A.S.
      • Kumararatne D.S.
      • Coles A.J.
      • Jones J.L
      Immune competence after alemtuzumab treatment of multiple sclerosis.
      ) To test T-cell-dependent antigen recall responses, IgG levels were measured before and 4 weeks after vaccinations with diphtheria and tetanus in 22 MS patients taking alemtuzumab, and in 21 patients taking alemtuzumab before and 4 weeks after inactivated polio 1, 2, and 3. Pre-vaccination, all had protection to diphtheria and TT that was maintained after alemtuzumab. Protection improved from 95% to 100% for polio 1 and from 77% to 95% for polio 3 after vaccination. At the time of vaccination, the median CD8 T-cell count was low and median CD4 T-cell and CD19 B-cell counts were normal. PPSV23 was used to test responses to T-cell–independent antigens. Of the 21 MS patients who were immunized, the proportion achieving seroconversion for serotypes 3 and 8 exceeded that of literature controls. Similarly, the proportion protected against Haemophilus influenzae type b and meningococcal group C (neoantigen) increased from 74% and 13%, respectively, to 100% and 91% post-vaccination, equivalent to published seroconversion rates for controls. The investigators noted that vaccination within 6 months of treatment resulted in a smaller proportion of responders. This study provides Level 3 evidence that response to prior vaccinations is maintained following alemtuzumab treatment, but suggests that vaccinations be delayed until at least at 6 months after alemtuzumab treatment.

      3.10 Effects of corticosteroids on responses to vaccines

      Several studies in non-MS patient populations (e.g. asthma, rheumatoid arthritis, systemic lupus erythematosus) have provided Level 3 evidence of minimal impact of chronic oral corticosteroids on vaccine responses. (
      • Briggs W.A.
      • Rozek R.J.
      • Migdal S.D.
      • et al.
      Influenza vaccination in kidney transplant recipients: cellular and humoral immune responses.
      ;
      • Lahood N.
      • Emerson S.S.
      • Kumar P.
      • Sorensen R.U
      Antibody levels and response to pneumococcal vaccine in steroid-dependent asthma.
      ;
      • Elkayam O.
      • Paran D.
      • Caspi D.
      • et al.
      Immunogenicity and Safety of Pneumococcal Vaccination in Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus.
      ,

      Wallin L., Quintilio W., Locatelli F., Cassel A., Silva M.B., Skare T.L. Safety and efficiency of influenza vaccination in systemic lupus erythematosus patients. Acta Reumatol. Port.. 34(3):498–502.

      ) However, the doses of corticosteroids in these studies were all lower than those typically used for MS relapses. In their 2013 guidelines, the Infectious Diseases Society of America recognized the lack of data on vaccine efficacy in people treated with high doses of corticosteroids (≥ 20 mg prednisone equivalents for ≥ 14 days). (
      • Rubin L.G.
      • Levin M.J.
      • Ljungman P.
      • et al.
      IDSA clinical practice guideline for vaccination of the immunocompromised host.
      ) It is generally recommended to avoid administering live vaccines during treatment with and until at least 4 weeks after discontinuing high-dose corticosteroids. (
      • Lebrun C.
      • Vukusic S
      Immunization and multiple sclerosis: recommendations from the French multiple sclerosis society.
      ;
      • Rubin L.G.
      • Levin M.J.
      • Ljungman P.
      • et al.
      IDSA clinical practice guideline for vaccination of the immunocompromised host.
      )

      3.11 Potential effects of MS disease-modifying therapies on responses to a SARS-CoV-2 vaccine

      Currently, many candidate SARS-CoV-2 vaccines of different types, including inactivated virus vaccines, subunit vaccines, non-replicating viral vector vaccines, and nucleic acid vaccines, are undergoing evaluation in clinical trials. (

      Draft landscape of COVID-19 candidate vaccines. Accessed June26, 2020. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines.

      ) Of note, effects of MS DMTs on immune responses to viral vector and nucleic acid vaccine types have not yet been reported. Also, few studies have addressed effects of DMTs on cellular immune responses to vaccinations. The duration of treatment with certain DMTs may also have an effect. This review addresses effects of MS DMTs on immune responses to existing vaccines as a guide to potential effects on a vaccine against SARS-CoV-2. However, the dearth of high-quality clinical data limits the strength of recommendations that can be made for an individual DMT. Given the key role of B cells in antibody development, anti-CD20 B cell-depleting therapies such as ocrelizumab are expected to limit the humoral responses to a SARS-CoV-2 vaccine. Vaccination data reviewed here provide some guidance, but the effects of DMTs on a SARS-CoV-2 vaccine will ultimately require prospective evaluation of humoral and cellular immune responses in people treated with specific DMTs.

      4. Conclusions

      This review addresses effects of MS DMTs on immune responses to existing vaccines. Existing studies indicate that, with the exception of beta-interferons, many MS DMTs blunt humoral immune responses to a variety of vaccine types. The opinion of the authors is that decision-making regarding DMTs should weigh the DMT efficacy against MS for the individual patient versus expected response to any vaccinations that may be needed in the future, including a SARS-CoV-2 vaccine.

      Funding

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

      Declaration of Competing Interest

      John R. Ciotti has received funding from the Biogen MS Clinical Fellowship Program.
      Manouela V. Valtcheva has nothing to disclose.
      Anne H. Cross is funded by the Manny & Rosalyn Rosenthal – Dr. John L. Trotter MS Center Chair in Neuroimmunology. She has also received consulting and/or speaking fees from Biogen, Celgene, EMD Serono, Genentech/Roche, Novartis and Race to Erase MS.

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