Infections, Vaccines and Autoimmunity: A Multiple Sclerosis Perspective

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease that is associated with multiple environmental factors. Among suspected susceptibility events, studies have questioned the potential role of overt viral and bacterial infections, including the Epstein Bar virus (EBV) and human endogenous retroviruses (HERV). Furthermore, the fast development of immunomodulatory therapies further questions the efficacy of the standard immunization policies in MS patients. Topics reviewed: This narrative review will discuss the potential interplay between viral and bacterial infections and their treatment on MS susceptibility and disease progression. In addition, the review specifically discusses the interactions between MS pathophysiology and vaccination for hepatitis B, influenza, human papillomavirus, diphtheria, pertussis, and tetanus (DTP), and Bacillus Calmette-Guerin (BCG). Data regarding potential interaction between MS disease modifying treatment (DMT) and vaccine effectiveness is also reviewed. Moreover, HERV-targeted therapies such as GNbAC1 (temelimab), EBV-based vaccines for treatment of MS, and the current state regarding the development of T-cell and DNA vaccination are discussed. Lastly, a reviewing commentary on the recent 2019 American Academy of Neurology (AAN) practice recommendations regarding immunization and vaccine-preventable infections in the settings of MS is provided. Conclusion: There is currently no sufficient evidence to support associations between standard vaccination policies and increased risk of MS. MS patients treated with immunomodulatory therapies may have a lower benefit from viral and bacterial vaccination. Despite their historical underperformance, new efforts in creating MS-based vaccines are currently ongoing. MS vaccination programs follow the set back and slow recovery which is widely seen in other fields of medicine.

[1]  M. Ramanathan,et al.  Higher EBV response is associated with more severe gray matter and lesion pathology in relapsing multiple sclerosis patients: A case-controlled magnetization transfer ratio study , 2020, Multiple sclerosis.

[2]  B. Serafini,et al.  Epstein-Barr Virus-Specific CD8 T Cells Selectively Infiltrate the Brain in Multiple Sclerosis and Interact Locally with Virus-Infected Cells: Clue for a Virus-Driven Immunopathological Mechanism , 2019, Journal of Virology.

[3]  A. Ascherio,et al.  Epstein–barr virus and multiple sclerosis risk in the finnish maternity cohort , 2019, Annals of neurology.

[4]  J. Sejvar,et al.  Practice guideline update summary: Vaccine-preventable infections and immunization in multiple sclerosis , 2019, Neurology.

[5]  M. Dougados,et al.  2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases , 2019, Annals of the rheumatic diseases.

[6]  P. Nilsson,et al.  Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk , 2019, Proceedings of the National Academy of Sciences of the United States of America.

[7]  C. Louapre,et al.  Immunization and multiple sclerosis: Recommendations from the French Multiple Sclerosis Society. , 2019, Revue neurologique.

[8]  S. Vukusic,et al.  Immunization and multiple sclerosis: Recommendations from the French multiple sclerosis society. , 2019, Multiple sclerosis and related disorders.

[9]  M. Ramanathan,et al.  Lifestyle-based modifiable risk factors in multiple sclerosis: review of experimental and clinical findings. , 2019, Neurodegenerative disease management.

[10]  N. Hattori,et al.  Adjuvant and antigenic properties of Mycobacterium avium subsp. paratuberculosis on experimental autoimmune encephalomyelitis , 2019, Journal of Neuroimmunology.

[11]  M. Ramanathan,et al.  The role of Epstein-Barr virus in multiple sclerosis: from molecular pathophysiology to in vivo imaging , 2019, Neural regeneration research.

[12]  Tan Tang,et al.  Harnessing the layer-by-layer assembly technique to design biomaterials vaccines for immune modulation in translational applications. , 2019, Biomaterials science.

[13]  H. Delecluse,et al.  Progress in EBV Vaccines , 2019, Front. Oncol..

[14]  L. Wilkins Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology , 2019, Neurology.

[15]  Katherine K. Matthews,et al.  Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosis , 2020, JCI insight.

[16]  M. Ramanathan,et al.  Interferon β for Multiple Sclerosis. , 2018, Cold Spring Harbor perspectives in medicine.

[17]  R. Benedict,et al.  Walking disability measures in multiple sclerosis patients: Correlations with MRI-derived global and microstructural damage , 2018, Journal of the Neurological Sciences.

[18]  I. Abdollahpour,et al.  Infectious exposure, antibiotic use, and multiple sclerosis: A population‐based incident case‐control study , 2018, Acta neurologica Scandinavica.

[19]  G. La Torre,et al.  HBV vaccine and risk of developing multiple sclerosis: a systematic review and meta-analysis , 2018, Human vaccines & immunotherapeutics.

[20]  M. Romano,et al.  Helicobacter pylori and extragastric diseases: A review , 2018, World journal of gastroenterology.

[21]  Zhaohui Wang,et al.  A novel PADRE-Kv1.3 vaccine effectively induces therapeutic antibodies and ameliorates experimental autoimmune encephalomyelitis in rats. , 2018, Clinical immunology.

[22]  M. Hecker,et al.  Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease‐modifying therapies , 2018, CNS neuroscience & therapeutics.

[23]  L. Steinman,et al.  Molecular signature of Epstein-Barr virus infection in MS brain lesions , 2018, Neurology: Neuroimmunology & Neuroinflammation.

[24]  F. Salvo,et al.  Human papillomavirus vaccine and demyelinating diseases—A systematic review and meta‐analysis , 2018, Pharmacological research.

[25]  R. Marrie,et al.  Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis , 2018, Neurology.

[26]  H. Hartung,et al.  Human Endogenous Retroviruses in Neurological Diseases , 2018, Trends in Molecular Medicine.

[27]  G. Khan,et al.  Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells , 2018, PloS one.

[28]  H. Olberg,et al.  Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy , 2018, European journal of neurology.

[29]  B. Sharrack,et al.  Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis , 2017, Neurology.

[30]  S. Sheikh,et al.  Immune response to vaccines is maintained in patients treated with dimethyl fumarate , 2017, Neurology: Neuroimmunology & Neuroinflammation.

[31]  R. Lucas,et al.  Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility , 2017, Neurology.

[32]  B. '. ’t Hart,et al.  EBV Infection Empowers Human B Cells for Autoimmunity: Role of Autophagy and Relevance to Multiple Sclerosis , 2017, The Journal of Immunology.

[33]  G. Freund,et al.  PNAS Plus Significance Statements , 2017, Proceedings of the National Academy of Sciences.

[34]  M. Ramanathan,et al.  Ocrelizumab: a B-cell depleting therapy for multiple sclerosis , 2017, Expert opinion on biological therapy.

[35]  N. Hattori,et al.  Altered humoral immunity to mycobacterial antigens in Japanese patients affected by inflammatory demyelinating diseases of the central nervous system , 2017, Scientific Reports.

[36]  M. Kulldorff,et al.  Evaluation of optic neuritis following human papillomavirus vaccination , 2017, Human vaccines & immunotherapeutics.

[37]  Kimberly Umans,et al.  Immune Response to Seasonal Influenza Vaccine in Patients with Relapsing-Remitting Multiple Sclerosis Receiving Long-term Daclizumab Beta: A Prospective, Open-Label, Single-Arm Study. , 2017, International journal of MS care.

[38]  C. L. Silva,et al.  pVAXhsp65 Vaccination Primes for High IL-10 Production and Decreases Experimental Encephalomyelitis Severity , 2017, Journal of immunology research.

[39]  C. Tench,et al.  The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis , 2017, PloS one.

[40]  G. Giovannoni,et al.  Epstein-Barr–negative MS: a true phenomenon? , 2017, Neurology: Neuroimmunology & Neuroinflammation.

[41]  B. '. ’t Hart,et al.  Analysis of the cross-talk of Epstein–Barr virus-infected B cells with T cells in the marmoset , 2017, Clinical & translational immunology.

[42]  J. Burrows,et al.  Defective T-cell control of Epstein–Barr virus infection in multiple sclerosis , 2017, Clinical & translational immunology.

[43]  S. Sharif,et al.  Marek’s disease in chickens: a review with focus on immunology , 2016, Veterinary Research.

[44]  S. V. van Kasteren,et al.  Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein , 2016, The Journal of Immunology.

[45]  R. Zivadinov,et al.  Use of natalizumab in multiple sclerosis: current perspectives , 2016, Expert opinion on biological therapy.

[46]  G. Gregoriadis,et al.  CD206-Targeted Liposomal Myelin Basic Protein Peptides in Patients with Multiple Sclerosis Resistant to First-Line Disease-Modifying Therapies: A First-in-Human, Proof-of-Concept Dose-Escalation Study , 2016, Neurotherapeutics.

[47]  R. Harris,et al.  Meta-analysis of association between Helicobacter pylori infection and multiple sclerosis , 2016, Neuroscience Letters.

[48]  S. Upala,et al.  Association between Helicobacter pylori infection and multiple sclerosis: A systematic review and meta-analysis. , 2016, Multiple sclerosis and related disorders.

[49]  M. Fitzpatrick,et al.  Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination , 2016, PLoS pathogens.

[50]  J. Chataway,et al.  Urinary tract infections in multiple sclerosis , 2016, Multiple sclerosis.

[51]  F. Curtin,et al.  MSRV envelope protein is a potent, endogenous and pathogenic agonist of human toll-like receptor 4: Relevance of GNbAC1 in multiple sclerosis treatment , 2016, Journal of Neuroimmunology.

[52]  Peter Nilsson,et al.  Anoctamin 2 identified as an autoimmune target in multiple sclerosis , 2016, Proceedings of the National Academy of Sciences.

[53]  Charles C. White,et al.  Genes and Environment in Multiple Sclerosis project: A platform to investigate multiple sclerosis risk , 2016, Annals of neurology.

[54]  M. Ramanathan,et al.  Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS , 2016, Neurology: Neuroimmunology & Neuroinflammation.

[55]  L. Kappos,et al.  A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients , 2015, Multiple sclerosis.

[56]  D. Wraith,et al.  Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS , 2015, Neurology: Neuroimmunology & Neuroinflammation.

[57]  Ashutosh Kumar Singh,et al.  Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis , 2015, Neurology.

[58]  M. Caligiuri,et al.  The Epstein–Barr Virus Lytic Protein BZLF1 as a Candidate Target Antigen for Vaccine Development , 2015, Cancer Immunology Research.

[59]  Cris S. Constantinescu,et al.  Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis , 2015, Journal of the Neurological Sciences.

[60]  B. Marshall,et al.  Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females , 2015, Journal of Neurology, Neurosurgery & Psychiatry.

[61]  H. Svanström,et al.  Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system. , 2015, JAMA.

[62]  F. Curtin,et al.  Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein , 2015, mAbs.

[63]  J. Cohen Epstein–barr virus vaccines , 2015, Clinical & translational immunology.

[64]  A. Langer-Gould,et al.  Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. , 2014, JAMA neurology.

[65]  R. Planas,et al.  Adoptive Transfer of EBV Specific CD8+ T Cell Clones Can Transiently Control EBV Infection in Humanized Mice , 2014, PLoS pathogens.

[66]  L. Kappos,et al.  Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial , 2014, The Lancet Neurology.

[67]  H. Olberg,et al.  Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study , 2014, Multiple sclerosis.

[68]  C. Pozzilli,et al.  Effects of Bacille Calmette-Guérin after the first demyelinating event in the CNS , 2014, Neurology.

[69]  L. Kappos,et al.  Preserved Antigen-Specific Immune Response in Patients with Multiple Sclerosis Responding to IFNβ-Therapy , 2013, PloS one.

[70]  H. Hartung,et al.  Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation , 2013, Annals of neurology.

[71]  A. Coles,et al.  Immune competence after alemtuzumab treatment of multiple sclerosis , 2013, Neurology.

[72]  K. Selmaj,et al.  Transdermal application of myelin peptides in multiple sclerosis treatment. , 2013, JAMA neurology.

[73]  A. Bar-Or,et al.  Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis , 2013, Neurology.

[74]  Sun-Whe Kim,et al.  Reduced antibody formation after influenza vaccination in patients with neuromyelitis optica spectrum disorder treated with rituximab , 2013, European journal of neurology.

[75]  D. Centonze,et al.  Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis , 2013, PLoS pathogens.

[76]  R. Reynolds,et al.  B-Cell Enrichment and Epstein-Barr Virus Infection in Inflammatory Cortical Lesions in Secondary Progressive Multiple Sclerosis , 2013, Journal of neuropathology and experimental neurology.

[77]  R. Manetti,et al.  Expression and Activation by Epstein Barr Virus of Human Endogenous Retroviruses-W in Blood Cells and Astrocytes: Inference for Multiple Sclerosis , 2012, PloS one.

[78]  S. Cohan,et al.  A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design , 2012, Multiple sclerosis.

[79]  H. Sørensen,et al.  Use of penicillin and other antibiotics and risk of multiple sclerosis: a population-based case-control study. , 2012, American journal of epidemiology.

[80]  L. Farinelli,et al.  Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease , 2012, Multiple sclerosis.

[81]  S. Reuter,et al.  DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. , 2012, The Journal of clinical investigation.

[82]  J. Correale,et al.  H1N1 vaccination does not increase risk of relapse in multiple sclerosis: a self-controlled case-series study , 2012, Multiple sclerosis.

[83]  A. Tierens,et al.  Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. , 2011, Blood.

[84]  J. Chataway,et al.  Relapse risk in patients with multiple sclerosis after H1N1 vaccination, with or without seasonal influenza vaccination , 2011, Journal of Neurology.

[85]  J. Melenhorst,et al.  Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects. , 2010, Blood.

[86]  K. Selmaj,et al.  Immune regulation of multiple sclerosis by transdermally applied myelin peptides , 2010, Annals of neurology.

[87]  A. Ascherio,et al.  Primary infection with the Epstein‐Barr virus and risk of multiple sclerosis , 2010, Annals of neurology.

[88]  S. Black,et al.  Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines , 2009, The Lancet.

[89]  J. Kira,et al.  Association of anti-Helicobacter pylori neutrophil-activating protein antibody response with anti-aquaporin-4 autoimmunity in Japanese patients with multiple sclerosis and neuromyelitis optica , 2009, Multiple sclerosis.

[90]  Dan R. Littman,et al.  Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria , 2009, Cell.

[91]  K. Schmierer,et al.  Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI , 2009, Neurology.

[92]  D. Rill,et al.  Autologous attenuated T-cell vaccine (Tovaxin) dose escalation in multiple sclerosis relapsing-remitting and secondary progressive patients nonresponsive to approved immunomodulatory therapies. , 2009, Clinical immunology.

[93]  A. Ascherio,et al.  Serum titers of IgG antibodies against tetanus and diphtheria toxoids and risk of multiple sclerosis , 2009, Journal of Neuroimmunology.

[94]  S. Suissa,et al.  Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood , 2009, Neurology.

[95]  M. Ramanathan,et al.  Epstein–Barr virus is associated with grey matter atrophy in multiple sclerosis , 2009, Journal of Neurology, Neurosurgery, and Psychiatry.

[96]  M. Li,et al.  Amelioration of experimental autoimmune encephalomyelitis by BLyS autovaccine. , 2008, Vaccine.

[97]  E. Radue,et al.  Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis , 2008, Annals of neurology.

[98]  S. Bay,et al.  Lipopentapeptide induces a strong host humoral response and distinguishes Mycobacterium avium subsp. paratuberculosis from M. avium subsp. avium. , 2008, Vaccine.

[99]  D. Bourdette,et al.  Therapeutic vaccination with a trivalent T‐cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis , 2008, Immunology.

[100]  M. Moutschen,et al.  Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. , 2007, The Journal of infectious diseases.

[101]  J. Ablin,et al.  Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response , 2007, Annals of the rheumatic diseases.

[102]  D. Arnold,et al.  Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. , 2007, Archives of neurology.

[103]  A. Bar-Or,et al.  Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study , 2007, The Lancet Neurology.

[104]  Gary Dubin,et al.  Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein-Barr virus vaccine in healthy adults. , 2007, Vaccine.

[105]  J. Fleming,et al.  Multiple sclerosis and the hygiene hypothesis , 2006, Neurology.

[106]  S. Suissa,et al.  Hepatitis B vaccine and risk of relapse after a first childhood episode of CNS inflammatory demyelination. , 2006, Brain : a journal of neurology.

[107]  S. Griffey,et al.  Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases , 2006, Proceedings of the National Academy of Sciences.

[108]  M. Hernán,et al.  Tetanus vaccination and risk of multiple sclerosis , 2006, Neurology.

[109]  M. Hernán,et al.  Antibiotic use and risk of multiple sclerosis. , 2006, American journal of epidemiology.

[110]  M. Lopez-Bresnahan,et al.  Immune response to influenza vaccine is maintained in patients with multiple sclerosis receiving interferon beta-1a , 2005, Neurology.

[111]  C. Guttmann,et al.  A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis , 2005, Multiple sclerosis.

[112]  P. Calabresi,et al.  The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[113]  A. Rickinson,et al.  CD8+ immunodominance among Epstein-Barr virus lytic cycle antigens directly reflects the efficiency of antigen presentation in lytically infected cells , 2005, The Journal of experimental medicine.

[114]  Terence Dwyer,et al.  Exposure to infant siblings during early life and risk of multiple sclerosis. , 2005, JAMA.

[115]  R. Peeling,et al.  A prospective study of Chlamydia pneumoniae infection and risk of MS in two US cohorts , 2004, Neurology.

[116]  W. Hammerschmidt,et al.  The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[117]  M. Tristem,et al.  The Evolution, Distribution and Diversity of Endogenous Retroviruses , 2003, Virus Genes.

[118]  Robert T. Chen,et al.  Vaccinations and risk of central nervous system demyelinating diseases in adults. , 2003, Archives of neurology.

[119]  D. Matchar,et al.  Immunization and MS: A summary of published evidence and recommendations , 2002, Neurology.

[120]  J. Bach,et al.  The effect of infections on susceptibility to autoimmune and allergic diseases. , 2002, The New England journal of medicine.

[121]  D Spiegelman,et al.  Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. , 2001, JAMA.

[122]  F. Hanefeld,et al.  Presence of Chlamydia pneumoniae DNA in the cerebral spinal fluid is a common phenomenon in a variety of neurological diseases and not restricted to multiple sclerosis , 2001, Annals of neurology.

[123]  V. ter meulen,et al.  Influenza vaccination in MS , 2001, Neurology.

[124]  S Suissa,et al.  Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. , 2001, The New England journal of medicine.

[125]  A M Walker,et al.  Hepatitis B vaccination and the risk of multiple sclerosis. , 2001, The New England journal of medicine.

[126]  P. Trillenberg,et al.  Association between clinical disease activity and Epstein–Barr virus reactivation in MS , 2000, Neurology.

[127]  L. Weiner,et al.  T cell vaccination in secondary progressive multiple sclerosis , 2000, Journal of Neuroimmunology.

[128]  A. Sadovnick,et al.  School-based hepatitis B vaccination programme and adolescent multiple sclerosis , 2000, The Lancet.

[129]  C. Pozzilli,et al.  Use of Bacille Calmette-Guèrin (BCG) in multiple sclerosis. , 1999, Neurology.

[130]  Amy S Orr,et al.  BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. , 1999, Science.

[131]  C. Stratton,et al.  Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis , 1999, Annals of neurology.

[132]  H. Garren,et al.  Suppressive immunization with DNA encoding a self-peptide prevents autoimmune disease: modulation of T cell costimulation. , 1999, Journal of immunology.

[133]  A. Gasbarrini,et al.  Regression of autoimmune thrombocytopenia after eradication of Helicobacter pylori , 1998, The Lancet.

[134]  E Marshall,et al.  A Shadow Falls on Hepatitis B Vaccination Effort , 1998, Science.

[135]  R. Knobler,et al.  A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis , 1997, Neurology.

[136]  Richard G Richards Interferon beta in multiple sclerosis , 1996, BMJ.

[137]  D. Bourdette,et al.  Treatment of multiple sclerosis with T–cell receptor peptides: Results of a double–blind pilot trial , 1996, Nature Medicine.

[138]  P. Stinissen,et al.  Depletion of myelin-basic-protein autoreactive T cells by T-cell vaccination: pilot trial in multiple sclerosis , 1995, The Lancet.

[139]  D. Bourdette,et al.  Immunity to TCR peptides in multiple sclerosis. I. Successful immunization of patients with synthetic V beta 5.2 and V beta 6.1 CDR2 peptides. , 1994, Journal of immunology.

[140]  D. Hafler,et al.  MHC-restricted depletion of human myelin basic protein-reactive T cells by T cell vaccination. , 1993, Science.

[141]  A. Antonovsky,et al.  Epidemiological study of multiple sclerosis in Israel. II. Multiple sclerosis and level of sanitation. , 1966, Journal of neurology, neurosurgery, and psychiatry.

[142]  J. Cohen Vaccine Development for Epstein-Barr Virus. , 2018, Advances in experimental medicine and biology.

[143]  X. Montalban,et al.  DNA-based vaccines for multiple sclerosis: current status and future directions. , 2012, Clinical immunology.

[144]  C. Kallenberg,et al.  Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab. , 2010, Arthritis and rheumatism.

[145]  Amy,et al.  VACCINATIONS AND THE RISK OF RELAPSE IN MULTIPLE SCLEROSIS , 2022 .