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

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

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

ABSTRACT

The Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology (DCNI/ABN) and Brazilian Committee for Treatment and Research in Multiple Sclerosis and Neuroimmunological Diseases (BCTRIMS) provide recommendations in this document for vaccination of the population with demyelinating diseases of the central nervous system (CNS) against infections in general and against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. We emphasize the seriousness of the current situation in view of the spread of COVID-19 in our country. Therefore, reference guides on vaccination for clinicians, patients, and public health authorities are particularly important to prevent some infectious diseases. The DCNI/ABN and BCTRIMS recommend that patients with CNS demyelinating diseases (e.g., MS and NMOSD) be continually monitored for updates to their vaccination schedule, especially at the beginning or before a change in treatment with a disease modifying drug (DMD). It is also important to note that vaccines are safe, and physicians should encourage their use in all patients. Clearly, special care should be taken when live attenuated viruses are involved. Finally, it is important for physicians to verify which DMD the patient is receiving and when the last dose was taken, as each drug may affect the induction of immune response differently.

Keywords:
Demyelinating Autoimmune Diseases, CNS; Multiple Sclerosis; Neuromyelitis Optica; Vaccination; COVID-19; SARS-CoV-2

RESUMO

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

INTRODUCTION

The Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology (DCNI/ABN) and Brazilian Committee for Treatment and Research in Multiple Sclerosis and Neuroimmunological Diseases (BCTRIMS) provide recommendations in this document for vaccination of the population with demyelinating diseases against infections in general and against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. These are not absolute recommendations, as there is yet no published evidence on the safety and efficacy of vaccines, particularly against SARS-CoV-2 and its variants in this population, but it may serve as a guide to vaccination. The text is based on the limited scientific evidence available, mainly centered on other autoimmune diseases and on expert opinion. However, for some specific vaccines, there are already more robust clinical trials related to the use of some disease-modifying drugs (DMDs), which are discussed in more detail below.

We emphasize the seriousness of the current moment in view of the progression of COVID-19 in our country, and refer to new variants of SARS-CoV-2, especially the P1 variant identified throughout the country, with the possibility of coinfection events occurring11. Faria NR, Mellan TA, Whittaker C, Claro IM, Candido D da S, Mishra S, et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science. 2021 May 21;372(6544):815-21. https://doi.org/10.1126/science.abh2644
https://doi.org/10.1126/science.abh2644...
. The participation of the entire medical and health community is essential to raise awareness of the importance of non-pharmacological measures associated with vaccination.

The history of vaccination in humans began in 1796 in the United Kingdom with the development of the smallpox vaccine22. Hussein IH, Chams N, Chams S, El Sayegh S, Badran R, Raad M, et al. Vaccines through centuries: major cornerstones of global health. Front Public Health. 2015 Nov 26;3:269. https://doi.org/10.3389/fpubh.2015.00269
https://doi.org/10.3389/fpubh.2015.00269...
. It is clear, therefore, that the experience and knowledge of the effects and safety of immunizations, especially in public health, are already scientifically consolidated33. Andre FE, Booy R, Bock HL, Clemens J, Datta SK, John TJ, et al. Vaccination greatly reduces disease, disability, death and inequity worldwide. Bull World Health Organ. 2008 Feb;86(2):140-6. https://doi.org/10.2471/blt.07.040089
https://doi.org/10.2471/blt.07.040089...
. Immunization should be understood as a way of exposing the immune system beforehand to a particular pathogen through its antigens, so that immune memory is developed and the body can respond more quickly in the case of infection, reducing the morbidity and mortality associated with the disease. Traditional forms of vaccination use live attenuated viruses, dead viruses or recombinant proteins, with or without polysaccharides44. Murphy K, Weaver C. Janeway’s Immunobiology. 9th edition. New York (NY): Garland Science; 2017. 887p. . Most of the existing vaccines available in the Brazilian National Immunization Program (NIP)55. Brasil, Ministério da Saúde. Instrução normativa referente ao Calendário de Vacinação 2020 [Internet]. 2020 [cited 2021 Mar 2];2:1-28. Available from: Available from: https://www.saude.gov.br/images/pdf/2020/marco/04/Instru----o-Normativa-Calend--rio-Vacinal-2020.pdf
https://www.saude.gov.br/images/pdf/2020...
and in several other countries use these techniques66. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tombly M, et al. Executive summary: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014 Feb 1;58:309-18. https://doi.org/10.1093/cid/cit816
https://doi.org/10.1093/cid/cit816...
. Unvaccinated individuals are at increased risk of morbidity and mortality by a given infectious disease and of spreading the infection.

An ideal vaccine should contain antigens targeted by the immune system, produce effective immunity (antibodies and T cells) and protective immunity, provide a good level of protection, preferably without the need for booster doses, cause few or no side effects, not cause illness or death, and be inexpensive, easy to administer and biologically stable44. Murphy K, Weaver C. Janeway’s Immunobiology. 9th edition. New York (NY): Garland Science; 2017. 887p. ,77. Montassier HJ. Vacinas e imunoterapia [Internet]. 2015 [cited 2021 Jan 10]. Available from: Available from: https://www.fcav.unesp.br/Home/departamentos/patologia/HELIOJOSEMONTASSIER/aula-12--vacinas-e-imunoterapia.pdf
https://www.fcav.unesp.br/Home/departame...
. During the current COVID-19 pandemic, other types of vaccines have been introduced, such as those with a non-replicating viral vector and with DNA or RNA of the pathogen (Table 1). Due to the great current importance of this subject, issues related to SARS-CoV-2 infection will be discussed later as a separate topic.

Table 1.
Characteristics of the main vaccine types.

Whenever the use of vaccines is addressed in the context of immune-mediated diseases, we must take into consideration two main issues. First, we must assess whether vaccines are safe in this population88. Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. Mult Scler Relat Disord. 2020 Oct 1;45:102439. https://doi.org/10.1016/j.msard.2020.102439
https://doi.org/10.1016/j.msard.2020.102...
. It is important to remember that after more than 200 years of use, there is no evidence that vaccination causes serious adverse events or deaths. Although there are reports of adverse effects, no causal link has been definitively established, and as such, the scientific community worldwide considers that the benefits of vaccination far outweigh the possible risks99. Miller ER, Moro PL, Cano M, Shimabukuro TT. Deaths following vaccination: What does the evidence show? Vaccine. 2015 Jun 26;33(29):3288-92. https://doi.org/10.1016/j.vaccine.2015.05.023
https://doi.org/10.1016/j.vaccine.2015.0...
. The second aspect concerns the individual's ability to generate or not generate an adequate protective immune response while using therapies that act on the immune system1010. Reyes S, Ramsay M, Ladhani S, Amirthalingam G, Singh N, Cores C, et al. Protecting people with multiple sclerosis through vaccination. Pract Neurol. 2020 Dec;20(6):435-45. https://doi.org/10.1136/practneurol-2020-002527
https://doi.org/10.1136/practneurol-2020...
,1111. 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.000000000000815
https://doi.org/10.1212/WNL.000000000000...
. It is important to note that this response can be affected in a totally different way, depending on the treatment used and the time interval since the last dose was received. In Brazil, it is recommended that the vaccination of individuals with Central Nervous System (CNS) immunological diseases not only comply with the recommendations of the NIP according to age groups, but also include coverage for some pathogens that can infect patients using immunosuppressive drugs, such as varicella zoster virus and encapsulated bacteria (i.e., pneumococci and meningococci)1212. Brasil, Ministério da Saúde. Manual dos centros de referência para imunobiológicos especiais [Internet]. 5th ed. Brasília: Ministério da Saúde; 2019 [cited 2021 Mar 10]. 174p. Available from: Available from: http://bvsms.saude.gov.br/bvs/publicacoes/manual_centros_imunobiologicos_%0Aespeciais_5ed.pdf
http://bvsms.saude.gov.br/bvs/publicacoe...
. It is important that the attending physician review the patient’s vaccination record at the initial consultation and at any planed DMDs change. The vaccination history should specifically include seasonal influenza, pneumococcus, hepatitis A and B, tetanus/diphtheria, varicella (chickenpox) and measles vaccination. Pre-vaccination serology testing for hepatitis A, hepatitis B, measles, rubella, and varicella zoster may also be necessary. Another important aspect is to assess the vaccination status of household contacts and close contacts of patients, especially those who use immunosuppressants and vaccinate contacts if necessary.

Several medical specialty societies and the American agency Center for Disease Control (CDC, USA) consider immunocompromised patients to be at high risk for the development of serious infectious diseases compared to immunocompetent individuals, whether they present permanent or reversible immune dysfunction66. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tombly M, et al. Executive summary: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014 Feb 1;58:309-18. https://doi.org/10.1093/cid/cit816
https://doi.org/10.1093/cid/cit816...
. The risks of developing serious forms of infectious diseases are related to conditions such as cancer, bone marrow transplant, solid organ transplant, genetic immunological deficiencies, human immunodeficiency virus (HIV), chronic use of intravenous or oral corticosteroids, and use of immunosuppressive medications, among others. The effectiveness of vaccination depends on the person’s intact immune response, especially concerning antigen function, activation of T and B lymphocytes, formation of plasma cells and antibodies production. Therefore, immunization may be less effective in immunocompromised patients compared to the general population44. Murphy K, Weaver C. Janeway’s Immunobiology. 9th edition. New York (NY): Garland Science; 2017. 887p. . Table 2 shows the main medications used for the treatment of demyelinating diseases of the CNS.

Table 2.
List of the main therapies available or in the process of approval in Brazil for the treatment of CNS autoimmune demyelinating diseases.

Regarding safety, vaccines containing inactivated virus, subunits, toxoid, nucleic acid and recombinant virus do not pose a risk in immunosuppressed patients, since they inoculate the inactivated pathogen or fragments of it. In transplant patients or patients with autoimmune diseases, there are no data indicating risk of transplant rejection or increased activity of the underlying autoimmune disease associated with vaccination66. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tombly M, et al. Executive summary: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014 Feb 1;58:309-18. https://doi.org/10.1093/cid/cit816
https://doi.org/10.1093/cid/cit816...
. Additionally, data on vaccination for other diseases do not indicate increased risks. In the specific case of Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorders (NMOSD), and other CNS demyelinating diseases, there is no causal association between any type of vaccine and risk of developing these autoimmune inflammatory conditions1010. Reyes S, Ramsay M, Ladhani S, Amirthalingam G, Singh N, Cores C, et al. Protecting people with multiple sclerosis through vaccination. Pract Neurol. 2020 Dec;20(6):435-45. https://doi.org/10.1136/practneurol-2020-002527
https://doi.org/10.1136/practneurol-2020...
,1111. 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.000000000000815
https://doi.org/10.1212/WNL.000000000000...
,1313. Lebrun C, Vukusic S. Immunization and multiple sclerosis: recommendations from the French Multiple Sclerosis Society. Rev Neurol (Paris). 2019 Jun;175(6):341-57. https://doi.org/10.1016/j.neurol.2019.04.001
https://doi.org/10.1016/j.neurol.2019.04...
. Most studies on vaccination and MS have been conducted with a seasonal influenza vaccine, including randomized placebo-controlled clinical trials that found no evidence of increased risk of MS after vaccine administration1414. Mokhtarian F, Shirazian D, Morgante L, Miller A, Grob D, Lichstein E. Influenza virus vaccination of patients with multiple sclerosis. Mult Scler J. 1997 Aug 1;3(4):243-7. https://doi.org/10.1177/135245859700300405
https://doi.org/10.1177/1352458597003004...
,1515. Zrzavy T, Kollaritsch H, Rommer PS, Boxberger N, Loebermann M, Wimmer I, et al. Vaccination in multiple sclerosis: Friend or foe? Front Immunol. 2019 Aug 7;10:1883. https://doi.org/10.3389/fimmu.2019.01883
https://doi.org/10.3389/fimmu.2019.01883...
.

Regarding vaccines with live attenuated viruses, there are reports of induced relapses in isolated cases, such as the yellow fever vaccine in patients with MS1010. Reyes S, Ramsay M, Ladhani S, Amirthalingam G, Singh N, Cores C, et al. Protecting people with multiple sclerosis through vaccination. Pract Neurol. 2020 Dec;20(6):435-45. https://doi.org/10.1136/practneurol-2020-002527
https://doi.org/10.1136/practneurol-2020...
,1313. Lebrun C, Vukusic S. Immunization and multiple sclerosis: recommendations from the French Multiple Sclerosis Society. Rev Neurol (Paris). 2019 Jun;175(6):341-57. https://doi.org/10.1016/j.neurol.2019.04.001
https://doi.org/10.1016/j.neurol.2019.04...
,1515. Zrzavy T, Kollaritsch H, Rommer PS, Boxberger N, Loebermann M, Wimmer I, et al. Vaccination in multiple sclerosis: Friend or foe? Front Immunol. 2019 Aug 7;10:1883. https://doi.org/10.3389/fimmu.2019.01883
https://doi.org/10.3389/fimmu.2019.01883...
. For this reason, the recommendation of this type of vaccine is made after assessing the benefits against the risk of inducing an exacerbation of the disease. It is important to emphasize that there is no causal association and, in most cases, the benefits outweigh the risks. Table 3 shows all available vaccines, including those accessible through the NIP and recommendations for use in patients with CNS demyelinating diseases.

Table 3.
Types of vaccines and recommendations for their use in patients with CNS demyelinating diseases.

CONSIDERATIONS ON THE EFFICACY OF VACCINES DURING TREATMENT WITH IMMUNOMODULATORY/ IMMUNOSUPPRESSIVE DRUGS

An effective immune response that provides long-term immune memory is generated primarily by the adaptive immune system, including B lymphocytes (humoral or antibody-mediated response) and T lymphocytes (cellular response). The humoral response is usually measured using serum IgG antibody levels against a specific antigen. The cellular response, on the other hand, is less studied, more complex, and methods for its evaluation vary in the literature44. Murphy K, Weaver C. Janeway’s Immunobiology. 9th edition. New York (NY): Garland Science; 2017. 887p. .

The immunomodulatory and immunosuppressive effects of different DMDs make assessment of vaccine efficacy more complex. The impact of these therapies on the adaptive immune system can decrease the response to vaccination by modifying the development of long-term immune memory88. Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. Mult Scler Relat Disord. 2020 Oct 1;45:102439. https://doi.org/10.1016/j.msard.2020.102439
https://doi.org/10.1016/j.msard.2020.102...
,1010. Reyes S, Ramsay M, Ladhani S, Amirthalingam G, Singh N, Cores C, et al. Protecting people with multiple sclerosis through vaccination. Pract Neurol. 2020 Dec;20(6):435-45. https://doi.org/10.1136/practneurol-2020-002527
https://doi.org/10.1136/practneurol-2020...
,1111. 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.000000000000815
https://doi.org/10.1212/WNL.000000000000...
,1313. Lebrun C, Vukusic S. Immunization and multiple sclerosis: recommendations from the French Multiple Sclerosis Society. Rev Neurol (Paris). 2019 Jun;175(6):341-57. https://doi.org/10.1016/j.neurol.2019.04.001
https://doi.org/10.1016/j.neurol.2019.04...
. Few studies have specifically addressed this issue and scientifically based recommendations do not yet exist for most existing therapies (Table 4).

Table 4.
Effect of main disease-modifying drugs in response to vaccination.

In general, the use of interferons beta and glatiramer acetate probably do not imply a reduction in seroprotection in response to influenza, tetanus, and diphtheria vaccines. On the other hand, the use of anti-CD20 monoclonal antibodies or fingolimod, for example, may result in decreased seroprotection in response to the influenza vaccine88. Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. Mult Scler Relat Disord. 2020 Oct 1;45:102439. https://doi.org/10.1016/j.msard.2020.102439
https://doi.org/10.1016/j.msard.2020.102...
. Given the lack of knowledge regarding the real impact of different DMDs on the effectiveness of particular vaccines, it may be appropriate to evaluate the seroprotection after vaccine administration for those patients under treatment and to consider the administration of booster doses, if necessary, after case-by-case evaluation. Whenever possible, evaluation of the vaccine-induced immune memory should be performed four weeks after application of the last recommended dose (expert opinion, level VII evidence).

VACCINATION FOR SARS-COV-2

Since January 2020, the world has been facing one of the worst pandemics. The SARS-CoV-2 virus has already infected millions of people globally and caused more than 2.5 million deaths. The only measures that can contain the spread of the virus are social distancing and isolation, frequent hand washing, and the correct use of masks3939. WHO. Coronavirus (COVID-19) Dashboard [Internet]. World Health Organization; 2021 [cited 2021 May 15]. Available from: Available from: https://covid19.who.int/
https://covid19.who.int/...
. This new infectious disease caused by the coronavirus (COVID-19), which causes severe acute coronavirus 2 respiratory syndrome (SARS-CoV-2), is a complex clinical syndrome that most often produces systemic manifestations and represents an ongoing challenge for neurologists who care for people with MS or NMOSD4040. Brownlee W, Bourdette D, Broadley S, Killestein J, Ciccarelli O. Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic. Neurology. 2020 Jun 2;94(22):949-52. http://doi.org/10.1212/WNL.0000000000009507
http://doi.org/10.1212/WNL.0000000000009...
. According to the World Health Organization (www.who.int), on November 3, 2020, there were 47 vaccine candidates under clinical evaluation and 155 vaccine candidates under preclinical evaluation.

Vaccines in development or already approved by regulatory agencies are formulated with nucleic acids (RNA or DNA), viral vector with adenovirus (non-replicating), inactivated virus or protein components of the virus - vaccine types that have no chance of viral replication - and consequently considered safe for use in immunosuppressed patients, without the need to suspend or modify the dosage of disease-modifying therapies cited below88. Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. Mult Scler Relat Disord. 2020 Oct 1;45:102439. https://doi.org/10.1016/j.msard.2020.102439
https://doi.org/10.1016/j.msard.2020.102...
,4141. Vetter V, Denizer G, Friedland LR, Krishnan J, Shapiro M. Understanding modern-day vaccines: what you need to know. Ann Med. 2018 Mar;50(2):110-20. https://doi.org/10.1080/07853890.2017.1407035
https://doi.org/10.1080/07853890.2017.14...
,4242. van Riel D, de Wit E. Next-generation vaccine platforms for COVID-19. Nat Mater. 2020 Aug;19(8):810-2. https://doi.org/10.1038/s41563-020-0746-0
https://doi.org/10.1038/s41563-020-0746-...
. As previously discussed, the use of live attenuated virus-based vaccines is not recommended in patients taking immunosuppressive therapies, should vaccines of this type against SARS-CoV-2 be approved in the future by any regulatory agency.

The shorter than usual approval time for these new vaccines can be explained by a number of factors. First, research on RNA vaccines began years prior to the emergence of the COVID-19 pandemic and many resources have been allocated for this purpose in a short period of time. Second, in comparison with traditional clinical trials, the results obtained have been evaluated quickly by regulatory agencies. This evaluation was performed as the data was produced and not just after completion of the entire study, as usually occurs.

Some examples of vaccines against SARS-CoV-2 already released by different international regulatory agencies include:

  • mRNA-based vaccines (Moderna and Pfizer/BioNTech), which promote an immune response against viral spike proteins;

  • Vaccines based on non-replicating adenovirus vector (CanSino, Gamaleya, Johnson & Johnson, Oxford-AstraZeneca), which increase the immune response against the coronavirus through a genetically modified vector that produces the spike glycoprotein;

  • Protein-based vaccines (Vector, Novavax, others), which induce an immune response against various proteins present in the coronavirus;

  • Inactivated virus-based vaccines (Sinopharm-Beijing, Sinopharm-Wuhan, Sinovac), which induce response to the different components of the inactivated coronavirus.

If there is no contraindication, immunosuppressed patients should be vaccinated due to the potential risk of developing severe forms of COVID-19 when infected with SARS-CoV-2. It is important to highlight that as of the beginning of February 2021, no international or national epidemiological study, such as that of the Brazilian Academy of Neurology (ABN) Brazilian Register of Neurological diseases (REDONE), has demonstrated an increased risk of serious COVID-19 disease in patients with MS and NMOSD treated with different DMDs or increased susceptibility for relapsing or CNS demyelination progression4343. REDONE.br - Neuroimmunology Brazilian Study Group Focused on COVID-19 and MS. Incidence and clinical outcome of Coronavirus disease 2019 in a cohort of 11,560 Brazilian patients with multiple sclerosis. Mult Scler J. 2021 Feb 2;1352458520978354. https://doi.org/10.1177/1352458520978354
https://doi.org/10.1177/1352458520978354...
.

There is currently no data on the effectiveness of the available vaccines in this group of individuals, as no clinical study with an adequate sample size of patients with these conditions has yet been conducted. Considering safety aspects, clinical studies of vaccines against SARS-CoV-2 do not indicate a relationship with the onset of CNS demyelinating inflammatory diseases in vaccinated individuals4444. Shimabukuro T. COVID-19 vaccine safety update [Internet]. National Center for Immunization & Respiratory Diseases, Centers for Disease Control and Prevention; 2021 [cited 2021 May 20]. Available from: Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-01/06-covid-shimabukuro.pdf
https://www.cdc.gov/vaccines/acip/meetin...
.

The main side effects that have been associated with approved vaccines for SARS-CoV-2 are low fever, myalgia, headache, nausea, fatigue, and pain/redness at the injection site. These effects are more frequent after the second dose (booster dose) of the vaccine and are self-limited4545. Agência Nacional de Vigilância Sanitária. Vacina COVID-19 (recombinante) [Internet]. FIOCRUZ; 2021 [cited 2021 May 20]. Available from: Available from: https://consultas.anvisa.gov.br/#/bulario/q/?nomeProduto=VACINA COVID-19
https://consultas.anvisa.gov.br/#/bulari...
,4646. Instituto Butantan. Vacina adsorvida COVID-19 (inativada) [Internet]. 2021 [cited 2021 May 20]. Available from: Available from: https://vacinacovid.butantan.gov.br/bulas
https://vacinacovid.butantan.gov.br/bula...
. Additional data will become available from time to time through existing vaccine monitoring programs in different countries. It is important to note that most vaccines have been tested on patients over 18 years of age, and none were tested on pregnant women.

Immunosuppressed patients vaccinated against COVID-19 should be advised about the potential for reduced effectiveness and, therefore, they should be advise to continue with protective measures, including social distancing, mask wearing, and hand washing and hygiene. People living with these patients should also be vaccinated to protect them.

Patients using DMDs who are known to have been infected with SARS-CoV-2, whether or not COVID-19 developed, should be vaccinated. Although some immune memory against the virus is to be expected, the immune response may be less efficient or even absent upon re-exposure to the virus.

Data on the efficacy of vaccination in patients with lymphopenia are limited, but there is evidence that it may reduce the effectiveness of the vaccine. Considering that the use of DMDs can lead to lymphopenia, physicians can make administration of the DMD more flexible, temporarily suspending or delaying the dose before beginning vaccination against COVID-19, resuming treatment after the vaccination schedule has been completed. Decisions must be made on individual basis, weighing the risks of suspending treatment against the underlying disease and the risk of severe COVID-19. Although there are no definitive recommendations for this group yet, and in the absence of a specific contraindication, vaccination should be considered rather than rejected, even in cases where the use of DMDs induces lymphopenia or more severe immunosuppression (less than 500 lymphocytes per ml of blood). Therefore, in the context of potential lymphopenia, it is recommended to request a complete blood count before immunization.

If there is no time to relax the administration of drugs, it is better to vaccinate and acquire a minimum degree of immunity against infection than otherwise. High vaccination rates in a community protect not only those who have been vaccinated, but also those who have not been vaccinated for some reason, whether or not they have developed immunity to the virus. This is the collective or 'herd' immunity that is so important in the fight against the SARS-CoV-2 pandemic.

In light of the above, the DCNI/ABN and BCTRIMS recommend that patients with MS or NMOSD be constantly monitored in terms of updating of their vaccination regimen, especially at the onset or before a change in DMD treatment. If the patient has vaccines pending, it is recommended that they be administered whenever possible before starting a DMD that may interfere with induction of immune memory. The safety of vaccines should be emphasized, and physicians should encourage their use in all patients. Clearly, special attention should be paid when live attenuated viruses are involved. Finally, it is important for physicians to verify which DMD the patient is taking and when the last dose was taken, as each drug may affect the induction of immune response differently.

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Publication Dates

  • Publication in this collection
    22 Nov 2021
  • Date of issue
    Nov 2021

History

  • Received
    24 Apr 2021
  • Accepted
    30 May 2021
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