Recomendações do Departamento Científico de Neuroimunologia da Academia Brasileira de Neurologia (DCNI/ABN) e do Comitê Brasileiro de Tratamento e Pesquisa em Esclerose Múltipla e Doenças Neuroimunológicas (BCTRIMS) sobre vacinação em geral e contra a SARS-CoV-2 para pacientes com doenças desmielinizantes do sistema nervoso central

Becker, Jefferson; Ferreira, Lis Campos; Damasceno, Alfredo; Bichuetti, Denis Bernardi; Christo, Paulo Pereira; Callegaro, Dagoberto; Peixoto, Marco Aurélio Lana; Sousa, Nise Alessandra De Carvalho; Almeida, Sérgio Monteiro De; Adoni, Tarso; Santiago-Amaral, Juliana; Junqueira, Thiago; Pereira, Samira Luisa Apóstolos; Gomes, Ana Beatriz Ayroza Galvão Ribeiro; Pitombeira, Milena; Paolilo, Renata Barbosa; Grzesiuk, Anderson Kuntz; Piccolo, Ana Claudia; D´Almeida, José Arthur Costa; Gomes Neto, Antonio Pereira; Oliveira, Augusto Cesar Penalva De; Oliveira, Bianca Santos De; Tauil, Carlos Bernardo; Vasconcelos, Claudia Ferreira; Kaimen-Maciel, Damacio; Varela, Daniel; Diniz, Denise Sisterolli; Oliveira, Enedina Maria Lobato De; Malfetano, Fabiola Rachid; Borges, Fernando Elias; Figueira, Fernando Faria Andrade; Gondim, Francisco De Assis Aquino; Passos, Giordani Rodrigues Dos; Silva, Guilherme Diogo; Olival, Guilherme Sciascia Do; Santos, Gutemberg Augusto Cruz Dos; Ruocco, Heloisa Helena; Sato, Henry Koiti; Soares Neto, Herval Ribeiro; Cortoni Calia, Leandro; Gonçalves, Marcus Vinícius Magno; Vecino, Maria Cecilia Aragón De; Pimentel, Maria Lucia Vellutini; Ribeiro, Marlise De Castro; Boaventura, Mateus; Parolin, Mônica Koncke Fiuza; Melo, Renata Brant De Souza; Lázaro, Robson; Thomaz, Rodrigo Barbosa; Kleinpaul, Rodrigo; Dias, Ronaldo Maciel; Gomes, Sidney; Lucatto, Simone Abrante; Alves-Leon, Soniza Vieira; Fukuda, Thiago; Ribeiro, Taysa Alexandrino Gonsalves Jubé; Winckler, Thereza Cristina D’ávila; Fragoso, Yara Dadalti; Nascimento, Osvaldo José Moreira Do; Ferreira, Maria Lucia Brito; Mendes, Maria Fernanda; Brum, Doralina Guimarães; Glehn, Felipe Von

doi:10.1590/0004-282X-ANP-2021-0162

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Brazilian Academy of Neurology • Arq. Neuro-Psiquiatr. 79 (11) • Nov 2021 • https://doi.org/10.1590/0004-282X-ANP-2021-0162 linkcopiar

Recomendações do Departamento Científico de Neuroimunologia da Academia Brasileira de Neurologia (DCNI/ABN) e do Comitê Brasileiro de Tratamento e Pesquisa em Esclerose Múltipla e Doenças Neuroimunológicas (BCTRIMS) sobre vacinação em geral e contra a SARS-CoV-2 para pacientes com doenças desmielinizantes do sistema nervoso central

Autoria SCIMAGO INSTITUTIONS RANKINGS

O DC de Neuroimunologia da ABN e o BCTRIMS trazem, nesse documento, as recomendações sobre vacinação da população com doenças desmielinizantes do sistema nervoso central (SNC) contra infecções em geral e contra o coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2), causador da COVID-19. Destaca-se a gravidade do atual momento frente ao avanço da COVID-19 em nosso País, o que torna mais evidente e importante a criação de guia de referência para orientação aos médicos, pacientes e autoridades de saúde pública quanto à vacinação, meio efetivo e seguro no controle de determinadas doenças infecciosa. O DCNI/ABN e o BCTRIMS recomendam que os pacientes com doenças desmielinizantes do SNC (ex., EM e NMOSD) sejam constantemente monitorados, quanto a atualização do seu calendário vacinal, especialmente, no início ou antes da mudança do tratamento com uma droga modificadora de doença (DMD). É importante também salientar que as vacinas são seguras e os médicos devem estimular o seu uso em todos os pacientes. Evidentemente, deve ser dada especial atenção às vacinas com vírus vivos atenuados. Por fim, é importante que os médicos verifiquem qual DMD o paciente está em uso e quando foi feita a sua última dose, pois cada fármaco pode interagir de forma diferente com a indução da resposta imune.

Palavras-chave:
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central; Esclerose Múltipla; Neuromielite Óptica; Vacinação; COVID-19; SARS-CoV-2

Type of vaccine	Live attenuated	Inactivated virus	Subunit	Toxoid	Nucleic acid	Recombinant vector
Mechanism	Made with whole pathogen, weakened under laboratory conditions	Uses the whole pathogen that has been inactivated in the laboratory	Uses the most immunogenic components of the pathogen	Uses inactivated bacterial toxins	Acts by encoding the RNA or DNA of the target antigen in order to produce antibodies	Employs an inactivated viral vector to introduce the pathogen's genetic material
Advantages	Provides strong humoral and cellular responses, conferring long-term immunity with one or two doses	Safe and stable as it contains no active virus	Safe and stable, as it contains no active pathogen	Safe and stable, as it contains no active pathogen	Stable and low-cost. Safe in principle, as it contains no active virus	More specific delivery of genes to target cells. Safe, in principle, as it contains no active virus
Disadvantages	Contraindicated in people with compromised immune systems, as it can induce reactivation of the pathogen and cause the disease	Provides a weaker immune response, which is why additional adjuvant or booster doses may be required	Increased cost, as the combination of antigens that will generate an effective response needs to be determined	Aims to protect against a specific toxin only. Does not provide collective protection and requires multiple doses to maintain protection	Induces limited response to antigen protein, thereby not being highly immunogenic	Can induce the formation of neutralizing antibodies that can reduce its effectiveness

Oral immunosuppressants	immunomodulators	Immunobiological/ venous immunosuppressants	Others
Azathioprine Cladribine Corticosteroids Fingolimod Dimethyl fumarate Methotrexate Mycophenolate mofetil Siponimod Teriflunomide	Glatiramer acetate Beta interferons	Alemtuzumab Cyclophosphamide Eculizumab Human immunoglobulin (intravenous) Inebilizumab Mitoxantrone Natalizumab Ocrelizumab Ofatumumab Rituximab Satralizumab	Gene therapies Autologous stem cell transplant

Vaccine	Vaccine type	Timetable recommended by the Brazilian Immunization Society (SBIm)	Recommendation for patients with MS/NMOSD
Acellular triple bacterial vaccine for adults Diphtheria-Tetanus-Pertussis (DTaP or DTaP-IVP) Diphtheria-Tetanus (DT) for adults	Diphtheria and tetanus toxoids Inactivated components of the Bordetella pertussis capsule	Update the DTaP regardless of previous DT or TT intervals. With complete basic vaccination regimen: DTaP boost every 10 years. With incomplete basic vaccination regimen: one dose of DTaP at any time and complete the basic vaccination with DT (double adult vaccine) in a total of three doses of vaccine containing the tetanus component. Unvaccinated and/or unknown vaccination history: one dose of DTaP and two doses of DT in regimen of 0 - 2 - 4 to 8 months. For individuals who intend to travel to countries where poliomyelitis is endemic: DTaP vaccine combined with inactivated polio (DTaP-IVP) is recommended. The DTaP-IVP can replace the DTaP.	Considered safe
HPV	Recombinant vaccine Virus particles	For unvaccinated adolescents ≥ 15 years of age, the regimen is 3 doses (0, 1-2, 6 months.) Two vaccines are available in Brazil: quadrivalent HPV, licensed for women aged 9 to 45 years and men aged 9 to 26 years; and bivalent HPV, licensed for women from 9 years of age.	Probably safe
Triple viral MMR (measles, mumps, rubella)	Live attenuated virus	Two doses of vaccine above 1 year of age, with minimum interval of one month between the two. For fully vaccinated adults, there is no evidence to justify a routine third dose, which can be considered in situations of a mumps and/or measles outbreak and disease risk	Probably safe, consider immunosuppression used
Meningococcal ACWY	Inactivated vaccine	Administer 2 (two) doses, at 3 (three) and 5 (five) months of age, with interval of 60 days between doses, minimum 30 days. Adolescents aged 11 and 12 years, administer 1 (one) booster dose or a single dose, according to their vaccination status. For unvaccinated adults: one dose	Probably safe
Meningococcal B	Recombinant vaccine	3 and 5 months of age and between 12 and 15 months. For adolescents not previously vaccinated, 2 doses one month apart are recommended. For adults up to 50 years of age, when justified: two doses with an interval of one to two months. After 50 years: use is off-label. High-risk groups, such as people living with HIV, or anatomic or functional asplenia, who have a complement deficiency or are using eculizumab or other biological drugs that interfere with the complement pathway: booster dose given three years after completing the vaccination regime	Probably safe
10-valent pneumococcal conjugate vaccine (VPC10) 13-valent pneumococcal conjugate vaccine (VPC13)	Inactivated vaccine	Routine vaccination with VPC10 or VPC13 is recommended for children from 2 months to 6 years of age. For children over 6 years of age, adolescents and adults with certain chronic diseases, the VPC13 and VPP23 vaccines are recommended. For those aged over 50 years, and especially over 60 years, the VPC13 and VPP23 vaccines are recommended	Probably safe
23-valent pneumococcal polysaccharide	Polysaccharide vaccine	From the age of 60 years, administer 1 (one) single additional dose, respecting a 5-year minimum interval from the initial dose.	Insufficient data
Herpes zoster	Live attenuated virus	Vaccine is licensed for people aged 50 + years and is recommended as routine for those over 60 years of age. Generally contraindicated in immune suppressed individuals	Insufficient data, consider immunosuppression used
Hepatitis B	Recombinant vaccine	Administer 1 (one) dose at birth, as early as possible in the first 24 hours, preferably in the first 12 hours after birth, still in the maternity ward. This dose can be administered up to 30 days after birth. Children from 7 (seven) years of age: Without vaccination proof: administer 3 (three) doses of hepatitis B vaccine with an interval of 30 days between the first and second dose, and 6 (six) months between the first and third dose (0, 1 and 6 months). With incomplete vaccination regimen: do not restart vaccination schedule, simply complete it according to the situation encountered. For pregnant women, any age group and gestational age: administer 3 doses of hepatitis B vaccine, considering the previous vaccination history and recommended intervals between doses. If it is not possible to complete the vaccination schedule during pregnancy, it must be completed after delivery	Considered safe
Hepatitis A	Inactivated vaccine	One dose administered at 15 months of age. For those children up to 4 years, 11 months and 29 days, who missed vaccination, administer one dose of hepatitis A vaccine. Case-by-case evaluation should be made of children with immunosuppression and those susceptible who fall outside the age range recommended in the National Vaccination Calendar	Considered safe
Inactivated Polio	Inactivated vaccine	Administer 3 (three) doses, at 2 (two), 4 (four) and 6 (six) months of age, with an interval of 60 days between doses. The minimum interval is 30 days between doses. Individuals 5 years of age or older without proof of vaccination or with an incomplete vaccination schedule should receive the OPV as an exception if they are residing in Brazil and will travel to areas with a vaccine recommendation.	Considered safe
Haemophilus influenzae type B (Pentavalent vaccine)	Conjugate vaccine	Administer 3 (three) doses, at 2 (two), 4 (four) and 6 (six) months of age, with an interval of 60 days between doses, minimum of 30 days. The third dose should not be administered before 6 (six) months of age. The pentavalent vaccine is contraindicated for children from 7 (seven) years of age.	Insufficient data
Yellow Fever	Live attenuated virus	Children from 9 (nine) months and younger than 5 (five) years of age: Administer 1 (one) dose at age 9 (nine) months, and a booster dose at 4 (four) years. Individuals from 5 (five) years to 59 years of age: Administer 1 (one) single dose. Conduct a risk-benefit assessment from 60 years of age. Yellow fever vaccine is usually contraindicated in immune suppressed patients (rheumatological diseases, malignant neoplasms, solid organ transplant, hematopoietic stem cell transplant), but it may be considered in certain situations depending on the degree of immunosuppression and epidemiological risk, with careful medical evaluation being necessary in such cases.	Probably increases the risk of an outbreak; the immunosuppression drug used should be considered
Influenza	Inactivated vaccine	For individuals from 9 (nine) years of age: administer 1 (one) dose annually during campaigns. Where available, the quadrivalent influenza vaccine (4V) is preferable to the trivalent influenza vaccine (3V), as it provides greater coverage of circulating strains.	Considered safe
Varicella (component of tetraviral vaccine available in the public health system)	Live attenuated viruses	Routinely recommended for children from 12 months of age onwards (use from 9 months onwards in exceptional circumstances, for example in situations of outbreak). All susceptible children, adolescents and adults (who have not had chickenpox) should be vaccinated	Probably safe, consider immunosuppression used

Medicines	Comments
Interferons beta	No change in humoral response when compared to healthy individuals. Tested for influenza, meningococcal, pneumococcal and DT⁸^,¹¹^,¹⁶^,¹⁷. Level III evidence American Academy of Neurology (AAN); or 3 Centre for Evidence-Based Medicine - University of Oxford (CEBM)
Glatiramer	Possible slight reduction in seroprotection in response to influenza vaccinations, when compared to healthy individuals or those using beta-interferons⁸^,¹¹^,¹⁷. Level III evidence (AAN); or 3 (CEBM)
Teriflunomide	Studies with small sample sizes have shown a slight reduction in immune response after vaccination against influenza and rabies¹⁶^,¹⁸. Level III evidence (AAN); or 2 (CEBM) The AAN recommendation is to not use live attenuated virus during treatment, or immediately before and up to 6 months after stopping treatment. Screening for tuberculosis (TB) and Varicella. Vaccinate for varicella (immune susceptible).
Dimethyl fumarate	A small sample study showed no difference in humoral response to vaccination, when compared to individuals using beta-interferons (DT, meningococcal and pneumococcal)¹⁹. Level III evidence (AAN); or 3 (CEBM) Post-hoc analysis of a subgroup of patients showed no relationship between lymphocyte count and response to vaccination¹⁹. Level IV evidence (AAN); or 4 (CEBM)
Fingolimod	Reduced immune response against influenza (A and B) and tetanus vaccines, when compared to patients using beta-interferons or healthy individuals¹⁷^,²⁰^-²². Level I/II evidence (AAN); or 2 (CEBM) Screening for hepatitis B. Vaccinate for varicella (immune susceptible). There may be a reduction in antibody titers produced by the vaccine after initiation of treatment with fingolimod²³. Level III evidence (AAN); or 3 (CEBM).
Natalizumab	Some studies suggest a reduced immune response against influenza and tetanus vaccines in a percentage of patients using natalizumab, when compared to those using beta-interferons or healthy individuals¹⁷^,²¹^,²⁴^,²⁵. Level III evidence (AAN); or 3 (CEBM)
Ocrelizumab	The VELOCE study showed a reduction in immune response and seroconversion rate in patients treated with ocrelizumab compared to patients using beta-interferons or without treatment (tetanus, pneumococcal, meningococcal and influenza vaccines were evaluated)²⁶. Level II evidence (AAN); or 2 (CEBM). Vaccinate with live attenuated virus vaccine at least 4 weeks before starting treatment and 2 weeks before for other vaccines. If the patient is already using ocrelizumab, the vaccine should ideally be applied between the 3rd and 5th month after the last infusion, so that induction of immune memory is more effective. In the event that additional doses are required, it is recommended that both or at least one of them be performed in this time window (expert opinion). Level 5 evidence (CEBM). The AAN recommendation is not to use a live attenuated virus vaccine during treatment, or immediately before and up to 6 months after stopping treatment. Screening for hepatitis B.
Ofatumumab	Insufficient data. Consider immunization schedule for immunocompromised patients (expert opinion). Level 5 evidence (CEBM). Live attenuated virus vaccines generally contraindicated. In the absence of specific studies for ofatumumab, the authors recommend observing the same recommendations made for ocrelizumab (expert opinion).
Alemtuzumab	Insufficient data on medication interference in the humoral response after vaccination. A small study suggests that humoral responses to vaccination performed prior to treatment are maintained²⁷. Level IV evidence (AAN); or 4 (CEBM) Prophylaxis for herpes at the start of treatment for up to 2 months or until lymphocyte > 200. Screening for TB and varicella, vaccination for varicella before starting treatment. Immunization should be performed at least 4 to 6 weeks before infusion of alemtuzumab. If the patient has already used the medication, wait at least 3 months, and if possible 6 months, to perform the vaccination (expert opinion). The AAN recommendation is to not use live attenuated virus vaccine during treatment or immediately before, and up to 6 months after stopping treatment
Cladribine	Insufficient data. A recent small study showed that MS patients treated with cladribine achieved seroprotection levels after influenza vaccination, but only 33% met seroconversion criteria²⁸. Level IV evidence (AAN); or 4 (CEBM) Consider immunization schedule for immunocompromised patients (expert opinion). Live attenuated virus vaccines generally contraindicated. Immunization should be performed at least 4 to 6 weeks before administration of cladribine. If patient has already used the medication, wait a minimum of at least 3 months, and if possible 6 months from the last dose before carrying out vaccination (expert opinion). Level 5 evidence (CEBM)
Cyclophosphamide	Insufficient data. Consider immunization schedule for immunocompromised patients (expert opinion). Level 5 evidence (CEBM).
Rituximab	The use of rituximab in studies of patients with rheumatoid arthritis has been associated with a reduction in humoral response and seroconversion rate to influenza and pneumococcal vaccines²⁹^-³¹. Level III evidence (AAN); or 3 (CEBM) A study of patients with NMOSD showed similar data to the influenza vaccine³². Level III evidence (AAN); or 3 (CEBM) Live attenuated virus vaccines are generally contraindicated. In the absence of specific studies for rituximab, the authors recommend observing the same recommendations made for ocrelizumab (expert opinion).
Azathioprine	Studies in patients with inflammatory bowel disease suggest that patients treated with azathioprine have a normal response to pneumococcal, tetanus and Haemophilus influenzae type B vaccines, but may have a reduced response to the hepatitis B vaccine³³^,³⁴. Level III evidence (AAN); or 3 (CEBM) Consider immunization schedule for immunocompromised patients (expert opinion). Level 5 evidence (CEBM). Live attenuated virus vaccines generally contraindicated.
Mycophenolate mofetil	Studies in kidney transplant patients with mycophenolate use suggest a reduction in humoral response and seroconversion rate for influenza vaccine (Mulley WR et al Kidney Int 2012; Tsujimura K et al Transplant Proc 2018). Level III evidence (AAN); or 3 (CEBM) Consider immunization schedule for immunocompromised patients (expert opinion). Level 5 evidence (CEBM). Live attenuated virus vaccines generally contraindicated.
Methotrexate	Some articles show a reduction in humoral response and seroconversion to influenza and pneumococcal viruses in patients with rheumatoid arthritis³⁵^-³⁷. Level III evidence (AAN); or 3 (CEBM) Discontinuation of treatment for 2 weeks can improve response to the influenza vaccine³⁸. Level II evidence (AAN); or 2 (CEBM) Consider immunization schedule for immunocompromised patients (expert opinion). Level 5 evidence (CEBM). Live attenuated virus vaccines generally contraindicated.
Corticosteroids	Live attenuated virus vaccines are contraindicated within 3 months after treatment discontinuation for adults using 20mg/day or children using 2mg/kg/day for more than 2 weeks. If the patient has used corticosteroids in high doses, there should be a gap of at least 15 days before carrying out the vaccination (expert opinion). Level 5 evidence (CEBM).
Eculizumab	Insufficient data. Consider immunization schedule for immunocompromised patients (expert opinion). Level 5 evidence (CEBM). Live attenuated virus vaccines generally contraindicated. Patients need to receive vaccines for meningococcus at least 2 weeks before starting treatment. If medication needs to be started sooner than this, prophylactic treatment should be given for 2 weeks
Inebilizumab	Insufficient data. Consider immunization schedule for immunocompromised patients (expert opinion). Level 5 evidence (CEBM). Live attenuated virus vaccines generally contraindicated. In the absence of specific studies for inebilizumab, the authors recommend observing the same recommendations made for ocrelizumab (expert opinion)
Satralizumab	Insufficient data. Consider immunization schedule for immunocompromised patients (expert opinion). Level 5 evidence (CEBM). Live attenuated virus vaccines generally contraindicated

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