key: cord-298668-ry49o0xj authors: Ciotti, John Robert; Valtcheva, Manouela V.; Cross, Anne Haney title: Effects of MS disease-modifying therapies on responses to vaccinations: a review. date: 2020-08-01 journal: Mult Scler Relat Disord DOI: 10.1016/j.msard.2020.102439 sha: doc_id: 298668 cord_uid: ry49o0xj 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. 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. 1 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. 2 Table 1 summarizes vaccine types and how the immune responses they generate differ. 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. 3 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. 4 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. 5 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) Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. 5 vaccines were all implicated and subsequently refuted as being linked to MS development or worsening. [6] [7] [8] [9] [10] [11] [12] [13] 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). 8 Regulatory bodies now recommend vaccinating people with MS on a normal schedule, with some caveats regarding live attenuated vaccines. [14] [15] [16] 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. 17 This review evaluates the current evidence regarding the impact of DMTs for MS on vaccine responses in humans. 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. 18 Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. 6 Table 2 provides a summary of all published studies of vaccine responses in people using FDA-approved DMTs for MS. 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. 19 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 teriflunomidetreated relapsing MS patients to 46 beta-interferon-treated relapsing MS patients. 20 For all 3 influenza strains used, >90% of those in the beta-interferon group had protective HI titers 28 days postvaccination. 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. 21 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 gammainterferon in response to influenza antigen, with no differences between groups. Level 3 evidence. The same investigator group performed another observational study of 25 MS patients taking betainterferons and compared influenza vaccine responses at multiple post-vaccination intervals to 62 HC. 23 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. 24 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 Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. 8 to MCV4 were not different, with 53% of each group demonstrating a 2-fold rise in IgG. Post-to prevaccination 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. 25 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. 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. A study already mentioned in the beta-interferon section investigated the effect of teriflunomide on influenza vaccination responses in MS patients. 20 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% Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. 10 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 betainterferon 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. 26 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. 3.4.1. Dimethyl fumarate. A single open-label, multicenter, non-randomized study evaluated the effects of dimethyl fumarate treatment on vaccination responses. 24 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 betainterferons above and provided Level 3 evidence that dimethyl fumarate treatment did not reduce T-cell dependent and humoral immune responses. 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). 28 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 placebotreated 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. 23 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. Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. 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. 25 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. 29 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 Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. 13 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. No relevant studies have been reported in MS patients on oral cladribine. A vaccine study is being planned by the manufacturer. An early study of 17 natalizumab-treated MS patients (14 female) and 10 HC (5 female) examined antibody response to seasonal influenza vaccination. 30 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). 31 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. Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. 14 A previously mentioned real-world study of 113 MS patients and 216 HC examined response to the 2009 H1N1 pandemic "swine flu" vaccine. 22 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. 23 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. In the previously-discussed 2019 non-randomized, prospective, study of 102 MS patients who underwent seasonal influenza vaccination, 14 were on natalizumab. 25 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. 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 2,000 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. 33 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. 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. 34 To test T-celldependent 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 Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. 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. 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. [35] [36] [37] [38] 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). 39 It is generally recommended to avoid administering live vaccines during treatment with and until at least 4 weeks after discontinuing high-dose corticosteroids. 15,39 This research did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors. Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. 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. The prevalence of MS in the United States: A population-based estimate using health claims data Fundamentals of vaccine immunology Measuring vaccine responses in the multiplex era Standardization of Hemagglutination Inhibition Assay for Influenza Serology Allows for High Reproducibility between Laboratories Sex and Gender Differences in the Outcomes of Vaccination over the Life Course Vaccines and multiple sclerosis: a systematic review Adverse Effects of Vaccines: Evidence and Causality Influenza vaccination in MS: Absence of T-cell response against white matter proteins Effects of MS disease-modifying therapies on responses to vaccinations: a review A multicenter, randomized, double-blind, placebocontrolled trial of influenza immunization in multiple sclerosis Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system Seasonal and H1N1v influenza vaccines in MS: safety and compliance Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases ACIP Altered Immunocompetence Guidelines for Immunizations | Recommendations | CDC Immunization and multiple sclerosis: Recommendations from the French multiple sclerosis society Infectious Complications of Multiple Sclerosis Therapies: Implications for Screening, Prophylaxis, and Management. Open forum Infect Dis Effects of MS disease-modifying therapies on responses to vaccinations: a review Vaccination against infection in patients with multiple sclerosis Immune response to influenza vaccine is maintained in patients with multiple sclerosis receiving interferon beta-1a Preserved antigen-specific immune response in patients with multiple sclerosis responding to IFNβ-therapy Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: An explorative study Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy Immune response to vaccines is maintained in patients treated with dimethyl fumarate Effects of MS disease-modifying therapies on responses to vaccinations: a review Immunization responses in rheumatoid arthritis patients treated with rituximab: Results from a controlled clinical trial Immune competence after alemtuzumab treatment of multiple sclerosis Influenza vaccination in kidney transplant recipients: Cellular and humoral immune responses Antibody levels and response to pneumococcal vaccine in steroid-dependent asthma Immunogenicity and Safety of Pneumococcal Vaccination in Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus Safety and efficiency of influenza vaccination in systemic lupus erythematosus patients IDSA clinical practice guideline for vaccination of the immunocompromised host Effects of MS disease-modifying therapies on responses to vaccinations: a review Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review.