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 occurring[1]. 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 vaccine[2]. It is clear, therefore, that the experience and knowledge of the effects and safety
of immunizations, especially in public health, are already scientifically consolidated[3]. 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 polysaccharides[4]. Most of the existing vaccines available in the Brazilian National Immunization
Program (NIP)[5] and in several other countries use these techniques[6]. 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
stable[4],[7]. 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.
|
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
|
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 population[8]. 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 risks[9]. 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
system[10],[11]. 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)[12]. 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 dysfunction[6]. 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 population[4]. [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.
|
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
|
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
vaccination[6]. 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 conditions[10],[11],[13]. 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 administration[14],[15].
Regarding vaccines with live attenuated viruses, there are reports of induced relapses
in isolated cases, such as the yellow fever vaccine in patients with MS[10],[13],[15]. 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.
|
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
|
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 literature[4].
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 memory[8],[10],[11],[13]. 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.
|
Medicines
|
Comments
|
|
Interferons beta
|
No change in humoral response when compared to healthy individuals. Tested for influenza,
meningococcal, pneumococcal and DT[8],[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-interferons[8],[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 rabies[16],[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 vaccination[19]. 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 individuals[17],[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 fingolimod[23]. 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 individuals[17],[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 maintained[27]. 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
criteria[28]. 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
vaccines[29]
-
[31]. Level III evidence (AAN); or 3 (CEBM) A study of patients with NMOSD showed similar
data to the influenza vaccine[32]. 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 vaccine[33],[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 arthritis[35]
-
[37]. Level III evidence (AAN); or 3 (CEBM) Discontinuation of treatment for 2 weeks
can improve response to the influenza vaccine[38]. 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
|
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 vaccine[8]. 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 masks[39]. 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 NMOSD[40]. 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
below[8],[41],[42]. 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 progression[43].
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 individuals[44].
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-limited[45],[46]. 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.
