Challenges and insights in immunization in patients with demyelinating diseases: a bench-to-bedside and evidence-based review

Desafios e insights na imunização de pacientes com doenças desmielinizantes: uma revisão da bancada à beira leito e baseada em evidências

Guilherme Diogo Silva Vítor Falcão de Oliveira Leonardo Oliveira Mendonça About the authors

ABSTRACT

Background:

Infections are among the main causes of death in patients with demyelinating diseases of the central nervous system (CNSDD). Vaccines are effective methods in reducing hospitalization and death from infectious diseases, but they are challenging in patients with CNSDD because of autoimmunity and immunosuppression.

Objectives:

To summarize the pathophysiological rationale and main evidence for vaccine recommendations in patients with CNSDD.

Methods:

Specialists with different backgrounds on the subject: a neurologist specialized in demyelinating diseases, an infectious diseases specialist and an immunologist, presented a critical narrative review of vaccination literature in patients with CNSDD, highlighting which vaccines should or should not be administered and the best time for it.

Results:

Patients with DDSNC are at increased risk of vaccine-preventable viral and bacterial infections. Vaccines can prevent herpes zoster, hepatitis B reactivation, HPV-associated warts and tumors, viral and bacterial pneumonia, and meningitis. Live attenuated virus vaccines should not be used when the patient is on immunosuppression. Vaccines should be avoided during relapses. The greatest vaccine efficacy is given before treatment or at the end of medication.

Conclusion:

Patients with DDSNC need differentiated immunization in relation to additional vaccines, contraindicated vaccines and timing of vaccination.

Keywords:
Vaccines; Demyelinating Diseases; Multiple Sclerosis; Immunization; Neuromyelitis Optica

RESUMO

Antecedentes:

Infecções estão entre as principais causas de morte de pacientes com doenças desmielinizantes do sistema nervoso central (DDSNC). Vacinas são métodos eficazes para reduzir internação e morte por doenças infecciosas, porém são desafiadoras em pacientes com DDSNC tanto pela autoimunidade quanto pela imunossupressão.

Objetivos:

Resumir o racional fisiopatológico e as principais evidências para as recomendações de vacinas em pacientes com DDSNC.

Métodos:

Especialistas com diferentes formações no tema: um neurologista especialista em doenças desmielinizantes, um infectologista e um imunologista, apresentam uma revisão crítica narrativa da Literatura de vacinação em pacientes com DDSNC, com destaque a quais vacinas devem ou não ser administradas e o melhor momento para isso.

Resultados:

Pacientes com DDSNC têm risco aumentado para infecções imunopreveníveis virais e bacterianas. Vacinas podem prevenir herpes zooster, reativação de hepatite B, verrugas e tumores associados ao HPV, pneumonias virais e bacterianas, além de meningites. Vacinas de vírus vivos atenuados não devem ser usadas quando o paciente está em uso de imunossupressão. Vacinas devem ser evitadas durante surtos. A maior eficácia vacinal é dada antes do tratamento ou ao final de doses de medicações.

Conclusão:

Os pacientes com DDSNC necessitam de imunização diferenciada em relação a vacinas adicionais, vacinas contraindicadas e melhor momento de vacinação.

Palavras-chave:
Vacinas; Doenças Desmielinizantes; Esclerose Múltipla; Imunização; Neuromielite Óptica

INTRODUCTION

Central Nervous System Demyelinating Diseases (CNSDD) are a heterogenous group of disorders with an acute or chronic inflammatory immunological process. This group of disorders is composed of the two most common forms, multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (here referred to as NMO) and also more rare conditions such as acute disseminated encephalomyelitis and myelin oligodendrocyte glycoprotein antibody-associated disease. Patients with CNSDD have been found to be at an increased risk of infectious diseases in large observational retrospective studies11. Luna G, Alping P, Burman J, Fink K, Fogdell-Hahn A, Gunnarsson M, et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 2020 Feb 1;77(2):184-91. https://doi.org/10.1001/jamaneurol.2019.3365
https://doi.org/10.1001/jamaneurol.2019....
. Moreover, infections are the leading cause of death in patients with multiple sclerosis22. Harding K, Zhu F, Alotaibi M, Duggan T, Tremlett H, Kingwell E. Multiple cause of death analysis in multiple sclerosis: a population-based study. Neurology. 2020 Feb 25;94(8):e820-9. https://doi.org/10.1212/WNL.0000000000008907
https://doi.org/10.1212/WNL.000000000000...
and neuromyelitis optica33. Du Q, Shi Z, Chen H, Zhang Y, Wang J, Qiu Y, et al. Mortality of neuromyelitis optica spectrum disorders in a Chinese population. Ann Clin Transl Neurol. 2021 Jul;8(7):1471-9. https://doi.org/10.1002/acn3.51404
https://doi.org/10.1002/acn3.51404...
.

Vaccines are an effective strategy to promote striking decreases in hospitalizations and deaths associated with infectious-preventable diseases44. Roush SW, Murphy TV; Vaccine-Preventable Disease Table Working Group. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. JAMA. 2007 Nov 14;298(18):2155-63. https://doi.org/10.1001/jama.298.18.2155
https://doi.org/10.1001/jama.298.18.2155...
. However, immunization in patients with CNSDD is complex. The disease per se and the immunosuppressive treatment can cause physicians and patients concerns such as precipitation of disease flares, severe adverse events after live attenuated vaccines, reduction of vaccine effectiveness, and the need for additional vaccines in a population with increased risk of infections55. Becker J, Ferreira LC, Damasceno A, Bichuetti DB, Christo PP, Callegaro D, et al. Recommendations by the Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology (DCNI/ABN) and the Brazilian Committee for Treatment and Research in Multiple Sclerosis and Neuroimmunological Diseases (BCTRIMS) on vaccination in general and specifically against SARS-CoV-2 for patients with demyelinating diseases of the central nervous system. Arq Neuropsiquiatr. 2021 Nov;79(11):1049-61. https://doi.org/10.1590/0004-282X-ANP-2021-0162
https://doi.org/10.1590/0004-282X-ANP-20...
.

In this review, we aim to propose a simplified approach, based on the actual evidence-based recommendations, experimental evidence, and the experience from experts from different specialties to guide the physicians who care for patients with CNSDD.

METHODS

Experts with different backgrounds in the field of vaccination in CNSDD patients provided a summary of relevant literature: a neurologist specialized in demyelinating diseases, an infectious diseases specialist and an immunologist. Articles were selected based on the experience of the experts and a non-systematic literature review using the terms: "vaccination", "immunization", "multiple sclerosis", "neuromyelitis optica", "demyelinating diseases" in Pubmed, Embase and Scopus.

For didactic reasons, we subdivided this review into sub-topics: additional vaccines that should be administered, vaccines that should not be administered, and the best time to administer the immunization.

RESULTS

Which vaccines should be administered in patients with CNSDD?

Patients with multiple sclerosis and neuromyelitis optica present with dysregulated immune-mediated responses that damage the CNS. Disease-modifying drugs (DMDs) can reduce the autoimmune response at the cost of harnessing the normal response against viral and bacterial agents. The two prototypical CNSDD are multiple sclerosis and neuromyelitis optica, this being the reason why we have focused our review-based analysis on these66. Jakimovski D, Weinstock-Guttman B, Ramanathan M, Dwyer MG, Zivadinov R. Infections, vaccines and autoimmunity: a multiple sclerosis perspective. Vaccines (Basel). 2020 Jan 28;8(1):50. https://doi.org/10.3390/vaccines8010050
https://doi.org/10.3390/vaccines8010050...
.

The autoimmune theory of the immunological response in patients with multiple sclerosis is widely studied and is characterized by the myelin self-reactive T-CD4 cells that migrate from the periphery to the CNS (also known as. the outside-in theory)77. Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018 Jan 11;378(2):169-80. https://doi.org/10.1056/NEJMra1401483
https://doi.org/10.1056/NEJMra1401483...
. These cells activate macrophages and microglia, leading to the damage of neurons and oligodendrocytes. This process leads to an epitope spreading, a process in which new myelin antigens are exposed, enhancing the theoretical autoimmune response (also known as the inside-out theory)77. Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018 Jan 11;378(2):169-80. https://doi.org/10.1056/NEJMra1401483
https://doi.org/10.1056/NEJMra1401483...
. Based on this theory, the treatment of multiple sclerosis involves drugs that target the aberrant immunological process of the self-reactive T-cells. Said that, drugs used are those that alter cytokine response (e.g. interferon beta), block myelin-specific antigen presentation (e.g. glatiramer acetate), block leukocyte migration into the CNS (e.g. S1P receptor modulators - fingolimod, siponimod, and posanimod - and cell adhesion agents - natalizumab), block B-cell dependent T-cell activation (e.g. anti-CD20 therapies - rituximab, ocrelizumab, and ofatumumab) or lead to B and T cell depletion (e.g. anti-CD52 strategies - alemtuzumab - or non-selective cytotoxic treatments - cladribine)88. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: a review. JAMA. 2021;325(8):765-79. https://doi.org/10.1001/jama.2020.26858
https://doi.org/10.1001/jama.2020.26858...
.

The autoimmune theory in patients with neuromyelitis optica is supported by the presence of serum-detectable levels of anti-aquaporin-4 autoantibodies that target astrocytes, culminating with the activation of the complement system and enhanced cytokine production (e.g. interleukin-6), considered the main mechanism of CNS damage99. Lucchinetti CF, Guo Y, Popescu BFG, Fujihara K, Itoyama Y, Misu T. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol. 2014 Jan;24(1):83-97. https://doi.org/10.1111/bpa.12099
https://doi.org/10.1111/bpa.12099...
. As previously said, the treatment of neuromyelitis optica includes anti-CD20 (e.g. rituximab) and anti-CD19 (e.g. inebilizumab) drugs that suppress the anti-aquaporin-4 autoantibodies production by B-cells; anti-C5 drugs (eculizumab) that inhibits the complement system; and anti-IL-6 (satralizumab or tocilizumab) that mitigates this cytokine production. Non-specific cytotoxic agents such as azathioprine, methotrexate and mycophenolate, considered to non-specifically block T-self reactive cells, are also used in these diseases1010. Huang W, Wang L, Zhang B, Zhou L, Zhang T, Quan C. Effectiveness and tolerability of immunosuppressants and monoclonal antibodies in preventive treatment of neuromyelitis optica spectrum disorders: a systematic review and network meta-analysis. Mult Scler Relat Disord. 2019 Oct 1;35:P246-52. https://doi.org/10.1016/j.msard.2019.08.009
https://doi.org/10.1016/j.msard.2019.08....
.

We highlight the importance of five viral vaccine-preventable agents in patients with CNS demyelinating diseases: varicella, hepatitis B, human papillomavirus (HPV), influenza and SARS-CoV-2.

The normal immune response to viral agents initiates with the activation of the innate immunity by the production of the interferon-type 1, the induced antiviral state followed by the viral neutralization mediated by antibodies and the cytotoxic killing of the infected cells by natural killer cells and TCD8 lymphocytes1111. Abbas AK, Lichtman AH, Pillai S. Preface. In: Abbas AK, Lichtman AH, Pillai S, editors. Cellular and molecular immunology. 10th ed. Elsevier; 2021. p. 5-7.. Any inherited or induced perturbations in the immunological process referred to here that allows viral escape of the immune response may cause life-threatening infections. Figure 1 summarizes the normal immune response to viral agents, the impact of DMDs and vaccine recommendations for clinical practice1212. Metze C, Winkelmann A, Loebermann M, Hecker M, Schweiger B, Reisinger EC, et al. Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease-modifying therapies. CNS Neurosci Ther. 2019 Feb;25(2):245-54. https://doi.org/10.1111/cns.13034
https://doi.org/10.1111/cns.13034...
.

Figure 1.
Normal immune response to viral agents, how disease-modifying drugs impact this response and what vaccine strategies we should implement.

As interferon-beta is a type-1 interferon, it is not expected that this DMD used in the treatment of multiple sclerosis compromises the normal antiviral response. Glatiramer acetate blocks the antigen presentation of myelin and it is not expected to compromise the normal immune response to the virus1212. Metze C, Winkelmann A, Loebermann M, Hecker M, Schweiger B, Reisinger EC, et al. Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease-modifying therapies. CNS Neurosci Ther. 2019 Feb;25(2):245-54. https://doi.org/10.1111/cns.13034
https://doi.org/10.1111/cns.13034...
.

On the other hand, patients with multiple sclerosis are at an increased risk of the use of herpes antiviral use in population studies11. Luna G, Alping P, Burman J, Fink K, Fogdell-Hahn A, Gunnarsson M, et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 2020 Feb 1;77(2):184-91. https://doi.org/10.1001/jamaneurol.2019.3365
https://doi.org/10.1001/jamaneurol.2019....
, particularly for patients using sphingosine-1 phosphate (S1P) receptor modulators such as fingolimod.

S1P receptor modulators have an anti-trafficking cell effect that results in an accumulation of lymphocytes in secondary immune lymph tissues and induces peripheral blood lymphopenia1313. Morris MA, Gibb DR, Picard F, Brinkmann V, Straume M, Ley K. Transient T cell accumulation in lymph nodes and sustained lymphopenia in mice treated with FTY720. Eur J Immunol. 2005 Dec 6;35(12):3570-80. https://doi.org/10.1002/eji.200526218
https://doi.org/10.1002/eji.200526218...
. Consequently it causes reduction of the VZV-specific T-cells inducing a subclinical reactivation in around 20% of the patients1414. Ricklin ME, Lorscheider J, Waschbisch A, Paroz C, Mehta SK, Pierson DL, et al. T-cell response against varicella-zoster virus in fingolimod-treated MS patients. Neurology. 2013 Jul 9;81(2):174-81. https://doi.org/10.1212/WNL.0b013e31829a3311
https://doi.org/10.1212/WNL.0b013e31829a...
and symptomatic infection was found to occur in 11 per 1000 patients1515. Arvin AM, Wolinsky JS, Kappos L, Morris MI, Reder AT, Tornatore C, et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015 Jan;72(1):31-9. https://doi.org/10.1001/jamaneurol.2014.3065
https://doi.org/10.1001/jamaneurol.2014....
.

Current guidelines recommend that a dose of the varicella zoster vaccine should be administered in individuals with varicella IgG negative antibodies and in those without a history of varicella infection1515. Arvin AM, Wolinsky JS, Kappos L, Morris MI, Reder AT, Tornatore C, et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015 Jan;72(1):31-9. https://doi.org/10.1001/jamaneurol.2014.3065
https://doi.org/10.1001/jamaneurol.2014....
. However, varicella zoster vaccine is a live attenuated virus vaccine and should be administered four to six weeks before the initiation of immunotherapy in order to avoid severe adverse events related to the vaccine.

Although to a lesser extent when compared with S1P receptor modulators, patients under rituximab and natalizumab therapy also present an increased risk of herpes antiviral use than the general population11. Luna G, Alping P, Burman J, Fink K, Fogdell-Hahn A, Gunnarsson M, et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 2020 Feb 1;77(2):184-91. https://doi.org/10.1001/jamaneurol.2019.3365
https://doi.org/10.1001/jamaneurol.2019....
. These monoclonal antibodies (anti-CD20, rituximab) seem to predispose to the risk of varicella-zoster virus infection as they reduce the humoral response against VZV1616. Mikulska M, Lanini S, Gudiol C, Drgona L, Ippolito G, Fernández-Ruiz M, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52). Clin Microbiol Infect. 2018 Jun 1;24 Suppl 2:S71-82. https://doi.org/10.1016/j.cmi.2018.02.003
https://doi.org/10.1016/j.cmi.2018.02.00...
, 1717. Redelman-Sidi G, Michielin O, Cervera C, Ribi C, Aguado JM, Fernández-Ruiz M, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Immune checkpoint inhibitors, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors). Clin Microbiol Infect. 2018 Jun;24(2 Suppl 2):S95-107. https://doi.org/10.1016/j.cmi.2018.01.030
https://doi.org/10.1016/j.cmi.2018.01.03...
. Cell adhesion inhibitors (natalizumab) compromise the cellular (CD4 and CD8 lymphocytes) surveillance in the CNS and may predispose not only to progressive multifocal leukoencephalopathy, a John Cunningham (JC) virus, but also to herpetic and varicella zoster encephalitis1818. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. Clin Infect Dis. 2013 Sep 15;57(6):849-52. https://doi.org/10.1093/cid/cit376
https://doi.org/10.1093/cid/cit376...
. Hence, varicella zoster vaccine should be considered for other immunosuppressants and not only S1P receptor modulators.

Hepatitis B virus reactivation is five times higher in patients under rituximab when compared with other immunosuppressive therapies1919. Evens AM, Jovanovic BD, Su YC, Raisch DW, Ganger D, Belknap SM, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011 May 1;22(5):1170-80. https://doi.org/10.1093/annonc/mdq583
https://doi.org/10.1093/annonc/mdq583...
. Indeed, in patients with multiple sclerosis, ocrelizumab was associated with reactivation of hepatitis B. Of note, CD-20 cell depletion impairs the B-cell dependent CD8 T-cell activation, reducing the cytotoxic defense against the hepatitis B virus2020. Lazdina U, Alheim M, Nyström J, Hultgren C, Borisova G, Sominskaya I, et al. Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent. J Gen Virol. 2003 Jan 1;84(1):139-46. https://doi.org/10.1099/vir.0.18678-0
https://doi.org/10.1099/vir.0.18678-0...
. Also, an immunological environment with suboptimal humoral and cellular responses to hepatitis B virus promotes viral replication and can cause immune-escape mutations2121. Ciardi MR, Iannetta M, Zingaropoli MA, Salpini R, Aragri M, Annecca R, et al. Reactivation of hepatitis B virus with immune-escape mutations after ocrelizumab treatment for multiple sclerosis. Open Forum Infect Dis. 2018 Dec 26;6(1):ofy356. https://doi.org/10.1093/ofid/ofy356
https://doi.org/10.1093/ofid/ofy356...
.

Hepatitis B vaccines derive from synthetic antigens developed from nucleotide sequence data to prepare large quantities of proteins by recombinant DNA technology1111. Abbas AK, Lichtman AH, Pillai S. Preface. In: Abbas AK, Lichtman AH, Pillai S, editors. Cellular and molecular immunology. 10th ed. Elsevier; 2021. p. 5-7.. Synthetic antigen vaccines are considered to be safe in patients using immunosuppressants. Current guidelines recommend that patients should test an Anti-HBs antibody prior to the initiation of anti-CD20 drugs. Patients with Anti-HBs negative antibodies should receive an additional jab of hepatitis B vaccine. However, patients with Anti-HBs antibody titers superior to 10 UI/mg should not receive an additional vaccine, but if a positive anti-HBc antibodies is found, antiviral prophylactic treatment should be considered to prevent hepatitis B virus reactivation for at least 12 months after the discontinuation of the immunotherapy2222. Tsutsumi Y, Yamamoto Y, Ito S, Ohigashi H, Shiratori S, Naruse H, et al. Hepatitis B virus reactivation with a rituximab-containing regimen. World J Hepatol. 2015 Sep 28;7(21):2344-51. https://doi.org/10.4254/wjh.v7.i21.2344
https://doi.org/10.4254/wjh.v7.i21.2344...
.

Case studies have suggested an association of the use of Fingolimod with HPV infection such as cutaneous warts, cervical and anogenital cancers2323. Triplett J, Kermode AG, Corbett A, Reddel SW. Warts and all: fingolimod and unusual HPV-associated lesions. Mult Scler. 2019 Oct 1;25(11):1547-50. https://doi.org/10.1177/1352458518807088
https://doi.org/10.1177/1352458518807088...
. The reduced immune response to viral infections and potential impaired cancer cells surveillance in patients receiving Fingolimod may explain this association2323. Triplett J, Kermode AG, Corbett A, Reddel SW. Warts and all: fingolimod and unusual HPV-associated lesions. Mult Scler. 2019 Oct 1;25(11):1547-50. https://doi.org/10.1177/1352458518807088
https://doi.org/10.1177/1352458518807088...
. Case studies have also described rapid progression of low-grade cervical dysplasia into invasive cancer in patients while on natalizumab therapy2424. Wan KM, Oehler MK. Rapid progression of low-grade cervical dysplasia into invasive cancer during natalizumab treatment for relapsing remitting multiple sclerosis. Case Rep Oncol. 2019 Jan 18;12(1):59-62. https://doi.org/10.1159/000496198
https://doi.org/10.1159/000496198...
, suggesting that cell adhesion inhibition might also compromise mucocutaneous defenses.

HPV vaccines are synthetic antigen vaccines produced by recombinant DNA technology and are considered safe in patients with CNSDD. Current guidelines recommend that patients aged between nine and 26, of either gender, should receive three doses (0, 2 and 6 months) of the HPV vaccine. Annual screening for cervical cancer should be considered for patients receiving immunosuppressants2323. Triplett J, Kermode AG, Corbett A, Reddel SW. Warts and all: fingolimod and unusual HPV-associated lesions. Mult Scler. 2019 Oct 1;25(11):1547-50. https://doi.org/10.1177/1352458518807088
https://doi.org/10.1177/1352458518807088...
.

The normal immune response to respiratory viruses such as SARS-CoV-2 and influenza are compromised in DMDs2525. Krammer F. The human antibody response to influenza A virus infection and vaccination. Nat Rev Immunol. 2019 Jun;19(6):383-97. https://doi.org/10.1038/s41577-019-0143-6
https://doi.org/10.1038/s41577-019-0143-...
. The production of effective neutralizing antibodies is not only affected by B-cell depleting agents2626. Bar-Or A, Calkwood JC, Chognot C, Evershed J, Fox EJ, Herman A, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study. Neurology. 2020 Oct 6;95(14):e1999-2008. https://doi.org/10.1212/WNL.0000000000010380
https://doi.org/10.1212/WNL.000000000001...
, but also by other immunotherapy strategies that compromise T-cell mediated B-cell activation such as Fingolimod2727. Kappos L, Mehling M, Arroyo R, Izquierdo G, Selmaj K, Curovic-Perisic V, et al. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology. 2015 Mar 3;84(9):872-9. https://doi.org/10.1212/WNL.0000000000001302
https://doi.org/10.1212/WNL.000000000000...
. The latter may also compromise the cytotoxic activation necessary for virus neutralization and eradication.

Current guidelines recommend that patients with CNSDD should receive an annual dose of the influenza vaccine. Vaccine against influenza is an inactivated vaccine and is considered safe in patients with CNSDD. However, current influenza vaccines do not induce broadly neutralizing antibodies that recognize multiple strains of the virus and thus short-life antibody-mediated protection explains why the vaccines should be administered annually2828. Lebrun C, Vukusic S; French Group for Recommendations in Multiple Sclerosis (France4MS) and the Société Francophone de la Sclérose En Plaques (SFSEP). Immunization and multiple sclerosis: recommendations from the French multiple sclerosis society. Mult Scler Relat Disord. 2019 Jun 1;31:173-88. https://doi.org/10.1016/j.msard.2019.04.004
https://doi.org/10.1016/j.msard.2019.04....
, 2929. Farez MF, Correale J, Armstrong MJ, Rae-Grant A, Gloss D, Donley D, et al. Practice guideline update summary: Vaccine-preventable infections and immunization in multiple sclerosis: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2019 Sep 24;93(13):584-94. https://doi.org/10.1212/WNL.0000000000008157
https://doi.org/10.1212/WNL.000000000000...
.

The management of patients with CNSDD during the COVID-19 pandemic was challenging. Multicentric observational retrospective studies demonstrated that patients with CNSDD presented a higher likelihood of hospitalization and intensive care unit admission compared with the general Brazilian population3030. Apostolos-Pereira SL, Ferreira LC, Boaventura M, Sousa NAC, Martins GJ, d'Almeida JA, et al. Clinical features of COVID-19 on patients with neuromyelitis optica spectrum disorders. Neurol Neuroimmunol Neuroinflamm. 2021 Aug 26;8(6):e1060. https://doi.org/10.1212/NXI.0000000000001060
https://doi.org/10.1212/NXI.000000000000...
. Different strategies such as telemedicine3131. Apóstolos-Pereira SL, Silva GD, Disserol CCD, Feo LB, Matos AMB, Schoeps VA, et al. Management of central nervous system demyelinating diseases during the coronavirus disease 2019 pandemic: a practical approach. Arq Neuropsiquiatr. 2020 Jul;78(7):430-9. https://doi.org/10.1590/0004-282X20200056
https://doi.org/10.1590/0004-282X2020005...
and oral methylprednisolone pulse therapy for relapses3232. Campana IG, Silva GD, Apóstolos-Pereira SL, Callegaro D. Successful treatment with 5-day oral 1 g/day methylprednisolone of optic neuritis and myelitis in AQP4 positive Neuromyelitis Optica: a report of two cases. Neuroimmunol Rep. 2021 Dec;1:100045. https://doi.org/10.1016/j.nerep.2021.100045
https://doi.org/10.1016/j.nerep.2021.100...
were performed, but no strategy was as successful as immunization.

Vaccines against SARS-Cov-2 can be inactivated (e.g. Coronavac), live viral vaccines involving recombinant non-replicant viruses (e.g. Astrazeneca), and RNA vaccines (e.g. Pfizer, Jansen). Live viral vaccines involving recombinant non-replicant virus have the advantage of inducing a full immune response similar to what occurs with live attenuated virus vaccines, but address safety concerns of live attenuated virus vaccines as they use a non-replicating vector. RNA vaccines activate RNA sensors and are amplified by lipid nanoparticles that act as adjuvant to enhance the immune response. In conclusion, all these technologies appear to be safe in patients with CNSDD. Multiple doses of these vaccines are recommended to allow a long-term response and the best schedule is still unknown.

The three most relevant bacterial vaccine-preventable agents in patients with CNS demyelinating diseases are Pneumococcus, Haemophilus, and Meningococcus. Figure 2 summarizes the normal immune response to bacterial agents, the impact of DMDs and the vaccine recommendations in clinical practice.

Figure 2.
Normal immune response to bacterial agents, how disease modifying drugs impact this response and what vaccine strategies we should implement.

The normal immune response to extracellular bacteria involves phagocytosis. Phagocytosis is amplified by other elements of the innate immune system, such as the C3b coating of bacteria, that allows for pore formation and consequently the lysis of microbes, a process mediated by the complement pathway. Phagocytosis is also amplified by the humoral response due to the opsonization and Fc receptor-mediated phagocytosis. Furthermore, adaptive cellular response, mediated by T CD4 lymphocytes, improves phagocytosis due to the intense release of pro-inflammatory cytokines such as IFN-gamma, IL-17, TNF-alpha1111. Abbas AK, Lichtman AH, Pillai S. Preface. In: Abbas AK, Lichtman AH, Pillai S, editors. Cellular and molecular immunology. 10th ed. Elsevier; 2021. p. 5-7..

Patients with multiple sclerosis are found to be at an increased risk of the use of antibiotics in population studies11. Luna G, Alping P, Burman J, Fink K, Fogdell-Hahn A, Gunnarsson M, et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 2020 Feb 1;77(2):184-91. https://doi.org/10.1001/jamaneurol.2019.3365
https://doi.org/10.1001/jamaneurol.2019....
, particularly with anti-CD20 monoclonal antibodies such as rituximab.

Anti-CD20 monoclonal antibodies can increase the risk of mild and severe respiratory infections because of secondary hypogammaglobulinemia and the reduction of the circulating B-cell dependent T-cell activation associated with cytokine release and antigen presentation3333. Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol. 2010 Apr;10(4):236-47. https://doi.org/10.1038/nri2729
https://doi.org/10.1038/nri2729...
. Two patients died from pneumonia in the randomized clinical trial that evaluated ocrelizumab in primary progressive multiple sclerosis3434. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-20. https://doi.org/10.1056/NEJMoa1606468
https://doi.org/10.1056/NEJMoa1606468...
. Large observational studies demonstrated that additional pneumococcal and haemophilus B vaccines can reduce the risk of respiratory infections in patients under rituximab3535. Moulis G, Lapeyre-Mestre M, Palmaro A, Sailler L. Infections in non-splenectomized persistent or chronic primary immune thrombocytopenia adults: risk factors and vaccination effect. J Thromb Haemost. 2017 Apr;15(4):785-91. https://doi.org/10.1111/jth.13622
https://doi.org/10.1111/jth.13622...
.

Pneumococcal vaccine (PV) can be composed of polysaccharide antigens or conjugated vaccine (polysaccharide coupled with protein). As polysaccharides are T-independent antigens, they tend to elicit low-affinity antibody responses and are best suited for boosters although not the first dosage. For this reason, it is recommended that the first dosage of pneumococcal vaccine should be PV13 vaccine (conjugated vaccine) with a booster dose of PV23 vaccine (polysaccharide vaccine), two months later3636. Principi N, Esposito S. Development of pneumococcal vaccines over the last 10 years. Expert Opin Biol Ther. 2018 Jan;18(1):7-17. https://doi.org/10.1080/14712598.2018.1384462
https://doi.org/10.1080/14712598.2018.13...
.

Eculizumab is an anti-C5 monoclonal antibody considered as a treatment option for neuromyelitis optica, preventing the aquaporin-4 mediated complement-induced damage3737. Pittock SJ, Berthele A, Fujihara K, Kim HJ, Levy M, Palace J, et al. Eculizumab in Aquaporin-4-Positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019 Aug 19;381(7):614-25. https://doi.org/10.1056/NEJMoa1900866
https://doi.org/10.1056/NEJMoa1900866...
. This drug causes a defective bactericidal complement activity used against encapsulated bacteria. The impact of deficient C5a-C9 is more evident in invasive meningococcal infections, leading to a 10,000-fold increase in the risk of invasive infection and an estimated meningococcal disease incidence of 1.5%3838. Winthrop KL, Mariette X, Silva JT, Benamu E, Calabrese LH, Dumusc A, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors). Clin Microbiol Infect. 2018 Jun 1;24 Suppl 2:S21-40. https://doi.org/10.1016/j.cmi.2018.02.002
https://doi.org/10.1016/j.cmi.2018.02.00...
. To mitigate this risk, it is recommended to perform additional boosters of meningococcal vaccine MenACWY every five years and of MenB every two to three years as long as an increased risk of meningococcal infection persists3939. Avasarala J, Sokola BS, Mullins S. Eculizumab package insert recommendations for meningococcal vaccinations: call for clarity and a targeted approach for use of the drug in neuromyelitis optica spectrum disorder. CNS Spectr. 2021 Jun;26(3):185-7. https://doi.org/10.1017/S1092852919001627
https://doi.org/10.1017/S109285291900162...
, 4040. Pittock SJ, Weitz I, Howard JF, Sabatella G, Mehta S, Franklin J. Response to: eculizumab package insert recommendations for meningococcal vaccinations: call for clarity and a targeted approach for use of the drug in neuromyelitis optica spectrum disorder. CNS Spectr. 2021 Jun;26(3):195-6. https://doi.org/10.1017/S1092852920001625
https://doi.org/10.1017/S109285292000162...
.

Which vaccines should not be administered in patients with CNSDD?

CNSDD is considered a disease of autoimmune phenomenon that occurs in genetically susceptible individuals who face environmental factors. As vaccines can induce autoimmune neurological adverse events, previous studies evaluated whether vaccines could induce an overall excess of cases of CNSDD.

In a large case-control study, vaccination against hepatitis B, influenza, tetanus, measles, or rubella was not associated with increased risk of multiple sclerosis or optic neuritis4141. DeStefano F, Verstraeten T, Jackson LA, Okoro CA, Benson P, Black SB, et al. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol. 2003 Apr;60(4):504-9. https://doi.org/10.1001/archneur.60.4.504
https://doi.org/10.1001/archneur.60.4.50...
. Systematic reviews confirmed that vaccines were not associated with central nervous system demyelination4242. Mouchet J, Salvo F, Raschi E, Poluzzi E, Antonazzo IC, De Ponti F, et al. Hepatitis B vaccination and the putative risk of central demyelinating diseases - a systematic review and meta-analysis. Vaccine. 2018 Mar 14;36(12):1548-55. https://doi.org/10.1016/j.vaccine.2018.02.036
https://doi.org/10.1016/j.vaccine.2018.0...
, 4343. Mouchet J, Salvo F, Raschi E, Poluzzi E, Antonazzo IC, De Ponti F, et al. Human papillomavirus vaccine and demyelinating diseases-A systematic review and meta-analysis. Pharmacol Res. 2018 Jun;132:108-18. https://doi.org/10.1016/j.phrs.2018.04.007
https://doi.org/10.1016/j.phrs.2018.04.0...
. Hence, no vaccine should be avoided as a public health concern of developing a CNSDD.

Another concern is that vaccines can induce relapse in patients who already present CNSDD. Systematic reviews from the American Academy of Neurology2929. Farez MF, Correale J, Armstrong MJ, Rae-Grant A, Gloss D, Donley D, et al. Practice guideline update summary: Vaccine-preventable infections and immunization in multiple sclerosis: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2019 Sep 24;93(13):584-94. https://doi.org/10.1212/WNL.0000000000008157
https://doi.org/10.1212/WNL.000000000000...
and the French Society of Neurology2828. Lebrun C, Vukusic S; French Group for Recommendations in Multiple Sclerosis (France4MS) and the Société Francophone de la Sclérose En Plaques (SFSEP). Immunization and multiple sclerosis: recommendations from the French multiple sclerosis society. Mult Scler Relat Disord. 2019 Jun 1;31:173-88. https://doi.org/10.1016/j.msard.2019.04.004
https://doi.org/10.1016/j.msard.2019.04....
found no association between vaccines and relapses in patients with multiple sclerosis. Even for the recent COVID-19 vaccines, cohort studies did not demonstrate an increased risk of relapse activity4444. Achiron A, Dolev M, Menascu S, Zohar DN, Dreyer-Alster S, Miron S, et al. COVID-19 vaccination in patients with multiple sclerosis: What we have learnt by February 2021. Mult Scler. 2021 May 1;27(6):864-70. https://doi.org/10.1177/13524585211003476
https://doi.org/10.1177/1352458521100347...
.

One exception to this rule is the yellow fever vaccine, a weak form of the virus, which was associated with increased relapse rate in travelers with multiple sclerosis2929. Farez MF, Correale J, Armstrong MJ, Rae-Grant A, Gloss D, Donley D, et al. Practice guideline update summary: Vaccine-preventable infections and immunization in multiple sclerosis: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2019 Sep 24;93(13):584-94. https://doi.org/10.1212/WNL.0000000000008157
https://doi.org/10.1212/WNL.000000000000...
. However, these studies were limited by small-size samples and further research is needed.

In patients with neuromyelitis optica, vaccines were associated with relapse in observational retrospective studies4545. Mealy MA, Cook LJ, Pache F, Velez DL, Borisow N, Becker D, et al. Vaccines and the association with relapses in patients with neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2018 Jul 1;23:78-82. https://doi.org/10.1016/j.msard.2018.05.003
https://doi.org/10.1016/j.msard.2018.05....
. Particularly, in this study, the risk was found to be low overall, estimated at 3% of patients, and persisting for 90 days following vaccination. However, this risk was not increased when patients were on adequate immunotherapy. Also the average risk of relapse was lower in adequately vaccinated patients than in patients who did not receive vaccination, possibly because infections can also trigger relapses.

The safety of live vaccinations in patients receiving immunotherapy is another concern. A systematic review4646. Croce E, Hatz C, Jonker EF, Visser LG, Jaeger VK, Bühler S. Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation - a systematic review of randomized trials, observational studies and case reports. Vaccine. 2017 Mar 1;35(9):1216-26. https://doi.org/10.1016/j.vaccine.2017.01.048
https://doi.org/10.1016/j.vaccine.2017.0...
including different immunosuppressed patients demonstrated that although the administration of live vaccines was safe in most patients, some can develop serious vaccine-related adverse events such as infection with the vaccine strain. The live vaccines that should be avoided in patients with CNSDD receiving DMDs include: mumps, measles, rubella, yellow fever, varicella vaccine/herpes zoster, oral polio, rotavirus, oral typhoid, smallpox and Bacillus Calmette-Guérin (BCG).

When is the best time to administer vaccines in patients with CNSDD?

Most vaccines work by inducing neutralizing antibodies. Vaccine-induced neutralizing antibodies are produced by long-life plasma cells and memory B-cells. These aspects of humoral response are best induced in the germinal center reaction, which requires cytokines and antigen presentation provided by protein antigen-specific CD4+ T follicular helper cells11. Figure 3 summarizes the normal vaccine-induced response, how DMDs impact this process and recommendations for clinical practice to optimize this process.

Figure 3.
Normal vaccine response and vaccine recommendations related to contraindications and timing.

Anti-CD20 monoclonal antibodies used in CNSDD can induce transitory or permanent depletion of multiple B-cell lineages and impair the production of neutralizing antibodies. In the VELOCE study2626. Bar-Or A, Calkwood JC, Chognot C, Evershed J, Fox EJ, Herman A, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study. Neurology. 2020 Oct 6;95(14):e1999-2008. https://doi.org/10.1212/WNL.0000000000010380
https://doi.org/10.1212/WNL.000000000001...
, the humoral response to non-live vaccines in patients with multiple sclerosis receiving ocrelizumab was attenuated when compared with patients receiving interferon beta or no immunotherapy.

As the vaccine-induced humoral response is optimized by the cellular response, it is expected that other DMDs may also impact the vaccine effectiveness. The S1P receptor modulation provided by Fingolimod compromises the cellular response against the vaccine antigens and, hence, impairs the T-cell-mediated activation of B-cells. In a populational study in England, the risk of SARS-Co-2 infection in patients with multiple sclerosis on Ocrelizumab or Fingolimod were increased when compared to the general population despite mass vaccination4747. Garjani A, Patel S, Bharkhada D, Rashid W, Coles A, Law GR, et al. Impact of mass vaccination on SARS-CoV-2 infections among multiple sclerosis patients taking immunomodulatory disease-modifying therapies in England. Mult Scler Relat Disord. 2022 Jan 1;57:103458. https://doi.org/10.1016/j.msard.2021.103458
https://doi.org/10.1016/j.msard.2021.103...
.

Therefore, the best time to administer vaccines in patients with CNSDD is before the introduction of any immunomodulatory therapy or at the end of the last dose of intermittent immunotherapies. For instance, for rituximab, the optimal timing for vaccination is at least three months after the last dose and at least one month before the next dose.

However, humoral responses after vaccines peaks after two to four weeks. For this reason, most guidelines recommend that vaccines should be administered up to four weeks before the start of the next dose of DMDs. Vaccines are usually contraindicated during flare-ups of CNSDD, despite the lack of studies on this subject. In an observational retrospective study, vaccines were associated with relapses in patients with neuromyelitis optica who are not on preventive immunotherapy but not among patients receiving adequate immunotherapy4545. Mealy MA, Cook LJ, Pache F, Velez DL, Borisow N, Becker D, et al. Vaccines and the association with relapses in patients with neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2018 Jul 1;23:78-82. https://doi.org/10.1016/j.msard.2018.05.003
https://doi.org/10.1016/j.msard.2018.05....
. A possible explanation is that adjunctives used in vaccines may increase the activity of autoreactive B and T lymphocytes causing flare-ups of CNSDD, particularly when immunotherapy is suboptimal such as during relapses. We provide a comparison of current guidelines regarding vaccination in patients with CNSDD in Table 1.

Table 1.
Comparison of current guidelines regarding vaccination in patients with CNSDD.

In conclusion, infections are the main cause of death in patients with CNSDD and can be prevented by vaccines. The evaluation of vaccine-preventable viruses should include varicella zoster, hepatitis B, HPV, influenza, and Sars-Cov-2. The evaluation of vaccine-preventable bacteria should include pneumococcus, haemophilus and meningococcal. Live-attenuated (e.g. measles or yellow fever) vaccines should be avoided. Vaccines should not be administered during flare-ups or, if possible, before the initiation of disease-modifying agents.

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Publication Dates

  • Publication in this collection
    12 Aug 2022
  • Date of issue
    May 2022

History

  • Received
    15 Mar 2022
  • Accepted
    29 Apr 2022
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