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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2745_Библиотеки_им_академика_М_И_Перельмана
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patients with MS are still often discouraged to get
vaccinations.
Two main concerns regarding immunizations are whether they
may trigger relapse activity or whether the patient is able to
mount a sufficient immune response to the vaccine. Use of the
hepatitis B vaccine in France had raised concern of increased
risk of MS relapse after this vaccination. The Vaccines in MS
Study (VACCIMUS) conducted by Confavareux et al. utilizing
the European Database for MS for vaccination history studied
tetanus, influenza, and hepatitis B and concluded that
vaccinations did not increase the short-term risk of relapse in
MS. 18 Mailand and Fredericksen in 2016 conducted a PubMed
literature review analyzing the risk of developing MS
following vaccinations. The study did not find any change in
the development of MS with vaccination against hepatitis B,
human papillomavirus (HPV), seasonal influenza, variola,
tetanus, measles mumps rubella, polio, diphtheria, or Bacillus
Calmette–Guérin (BCG).19 A case control study conducted by
DeStefano et al examining cases of MS or optic neuritis
among adults aged 18 to 49 years did not reveal any increased
risk of MS exacerbation or optic neuritis following vaccination
against hepatitis B, influenza, tetanus, measles, or rubella.
20
Live Attenuated Vaccines
Live attenuated vaccines are obtained from the virus or
bacteria and are weakened in the laboratory. A small dose of
the pathogen grows in the immunized host, and antibodies are
developed. These are generally not recommended.in MS
because the vaccine’s ability to cause disease has been
decreased but the vaccine is not entirely inactivated.
21
Exposure to a family member or child who has had live virus
injection and subsequent risk is not certain. The following are
examples of live attenuated vaccines.
Measles Mumps Rubella
Adult patients may need to have antibody titers checked. If the
titer is low, a booster dose should be given. This vaccine is
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generally safe when given to patients taking interferon
therapies and glatiramer acetate. However, because measles
mumps rubella is a live attenuated virus, it is not
recommended to be used during treatment with cell-depleting
therapies alemtuzumab, ocrelizumab, rituximab, and also
fingolimod, dimethyl fumarate, cladribine, and terifluonimide.
Varicella Vaccine
Varicella immunization appears to be safe for patients with
MS. Before treatment with fingolimod, if there is no evidence
of varicella antibodies, patients are required to have the
vaccine, wait 4 weeks, and then start taking fingolimod. All
nonimmune adults are recommended to have two doses of the
vaccine 4 to 8 weeks apart. Varicella vaccine in general is
recommended by the Centers for Disease Control and
Prevention (CDC) to be given to people of any age who are
seronegative for varicella. If patients have untreated or active
TB, they cannot get the vaccine but need to wait until the TB
is treated. It is also recommended before alemtuzumab use if
patient is IgG antibody negative. Live attenuated vaccine
should be given at least 4 weeks before ocrelizumab infusion.
Yellow Fever
Encephalitis and meningitis may occur following the vaccine.
Studies have shown an increased risk of relapses following the
yellow fever vaccine. Individuals taking immunosuppressant
medications should generally not use this vaccine.19 However,
this risk of increased relapses does need to be weighed against
the risk of contracting yellow fever, which is potentially fatal.
Generally, it is best to avoid this vaccine unless risk when
traveling to an endemic country (South America, Africa) is
great.
Bacillus Calmette–Guérin
One small pilot trial had suggested that the BCG vaccine could
reduce exacerbation in MS. However, in the United States, the
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CDC, because of the low risk of Mycobacterium tuberculosis
infection, does not generally recommend this.
Smallpox Vaccine
This is a live vaccine and is generally not recommended for
anyone with MS; however, if there is exposure, then the risk of
developing smallpox outweighs the risk of its use.
Other Live Attenuated Vaccines
Oral polio
Intranasal influenza
Oral typhoid-directed against bacteria
Inactivated Vaccines (Killed Microbes)
Inactivated vaccines, or “killed microbes,” in general are safer
to use than live attenuated vaccines, regardless of what DMT
the patient is taking.21 Oftentimes, repeated doses are given
because the immune response generated is weaker. Generally,
inactivated vaccines are considered safe to use in patients
taking interferon therapies, Aubagio, Copaxone, mitoxantrone,
Gilenya, Lemtrada, Tysabri, Tecfidera, Ocrevus, and Rituxan.
The following vaccines are inactivated whole virus vaccines
that are accepted for use in patients with MS:
Polio (injection)
Rabies
Hepatitis A
Varicella
Subunit and Conjugate Vaccines
Subunit vaccines involve microbial antigens that stimulate the
immune system. Conjugate vaccines are polysaccharides
attached to an antigen to boost efficacy and include conjugate
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polysaccharide vaccines (Haemophilus influenza type B,
pneumococcal, meningococcal) and meningococcal
quadrivalent conjugate and meningococcal polysaccharide
vaccines.
Influenza Vaccination (Seasonal Flu)
Two types of influenza vaccines are commonly used. The first
is the inactivated vaccine, which is typically used by most
facilities. The second is the live attenuated vaccine (nasal
spray). This should be avoided. The National MS Society has
stated in its guidelines that the seasonal flu vaccine is
considered safe and generally recommended in all patients
with MS, regardless of the DMT they are taking. Not only can
influenza infection worsen MS disease symptoms but also it is
associated with significant morbidity on its own.
22
The influenza vaccine is particularly recommended for
patients with MS who are nonambulatory, wheelchair or bedbound, use motorized scooters, and have impaired respiratory
function23 and is given on an annual basis. For patients who
are taking the cell-depleting therapies Lemtrada and rituximab,
the influenza vaccine should be given 6 weeks before the
infusion cycle. For Ocrevus, it should be administered at least
2 weeks before infusion. Note that it is only the inactivated flu
vaccine (standard dose) that is recommended. More data are
needed to make recommendations regarding the high-dose
inactivated flu vaccine (Fluzone High-Dose).
The immune response in patients receiving interferon beta1b/1a and glatiramer acetate was shown to be similar to that of
controls in the study done by Olberg.24 Regarding influenza
efficacy with natalizumab use, there have been conflicting
studies. One study done by Vagberg et al showed that a
humoral immune response to the influenza vaccination was
maintained in natalizumab-treated patients, and the study done
by Kaufman et al25 also showed no decrease in immune
response in relapsing patients treated with natalizumab.
However, a Norwegian study done by Olberg et al evaluated
90 patients who received fingolimod, glatiramer acetate,
interferon beta-1a/1b, natalizumab, or no therapy and
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compared them with 62 healthy controls. Serum samples were
collected before vaccination and 3, 6, and 12 months after
vaccination. The results showed reduced protection rates with
patients treated with natalizumab or fingolimod but not
interferon beta-1a/1b or glatiramer, suggesting that patients
receiving fingolimod or natalizumab should be considered for
a second dose of the flu vaccine.26 A vaccine study (study to
investigate the immune response to influenza vaccine in
patients with multiple sclerosis on teriflunomide) analyzing
humoral response rates following teriflunomide use showed
effective response, although it slightly decreased with the 14mg dose. Immune response was also maintained in patients
taking Tecfidera. The influenza vaccine is contraindicated in
patients who are allergic to eggs. Patients who have an acute
febrile illness or active infection should wait until they are
infection free before getting the vaccine. If a patient does
contract the flu, use of Tamiflu or antivirals such as
amantadine may be helpful in decreasing symptoms.
Hepatitis B Vaccine
For the hepatitis B vaccine, there are two to three vaccinations
recommended. This is considered safe in MS. The
VACCIMUS study group did not find any association between
hepatitis B vaccination and increased risk of relapse. The
Institute of Medicine study also found no association with the
onset of MS disease activity. According to the CDC
guidelines, the hepatitis B vaccine is recommended for all
children, teenagers, and adults who are at risk of contracting
this disease, that is:
Anyone working in a job that involves contact with
human blood
Anyone with diabetes and under age 60 years
Anyone living in a house or having sex with someone
who has hepatitis B infection
Anyone having sex with more than one partner
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People who live or travel outside the United States for
more than 6 months out of the year
A 2002 report by the Institute of Medicine did not find
any causal relationship between the hepatitis B vaccine
and development of MS
Human Papillomavirus Vaccine (Gardasil)
Inactivated
This is recommended for males and females for the prevention
of genital warts and anal and cervical cancer. There is a threedose series to the vaccine, the second and third doses given 2
and 6 months from the first dose. In a cohort study utilizing
nationwide registries in two Scandinavian countries conducted
by Scheller et al,27 HPV vaccinations were not associated with
the development of MS or other demyelinating illness. This
study included 3,983,824 females, aged 10 to 44 years, during
the years 2006 to 2013, among whom 789,082 received a total
of 1,927,581 HPV vaccine doses. This study added to the body
of data supporting a favorable overall safety profile of the
HPV vaccine. There was one case report,28 however, of acute
disseminated encephalomyelitis following the second
immunization with Gardasil. A recent large-scale study
utilizing patient registries in Denmark and Sweden among
nearly 800,000 patients who received the vaccine found no
increased risk of developing MS.
Zoster (Shingrix) Recombinant Vaccine
Subunit
The CDC recommendation for zoster vaccination is
administration of two doses of recombinant zoster vaccine
(RZV-Shingrix) 2 to 6 months apart to adults 50 years or older
regardless of prior history of herpes zoster or having received
the live zoster vaccine (Zostavax, ZVL). Recombinant
Shingrix vaccine is preferred in MS because of both its
increased safety and efficacy. The efficacy of Shingrix in
preventing zoster is 97.2% compared with Zostavax, a 51%
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decrease in preventing zoster. No studies have been done of
Shingrix in MS; however, no increase in autoimmune disease
was noted in two clinical studies with Shingrix.
The Zostavax vaccine is not recommended if a patient is
taking Aubagio. Zostavax in general is not recommended
because Shingrix has become available owing to improved
efficacy and decreased risk. Also, for Lemtrada use, the patient
would need to wait 6 weeks after receiving the vaccine before
getting Lemtrada.
Pneumococcal (Conjugate Polysaccharide
Vaccine)
Pneumovax 23 and Prevnar 13 are inactivated and considered
safe.
Generally, CDC guidelines for the general population are also
recommended for patients with MS, particularly for patients
who are wheelchair dependent who have impaired pulmonary
function. The humoral response after Lemtrada use was
similar to that of controls.
Other Subunit/Conjugated Vaccines
Typhoid
Tick-borne encephalitis
Toxoid Vaccine
Toxoid vaccines are derived from a toxin treated to destroy its
toxic properties but that can elicit an immune response to the
original toxin. Toxoid vaccines are present for diphtheria,
tetanus, and botulism.
Diphtheria, Tetanus Toxoids, and Pertussis
The CDC recommends that all adults be vaccinated for
diphtheria/tetanus. Tetanus vaccination appears to be safe for
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patients with MS. Tetanus booster should be given every
10 years (Table 6.2).
TABLE 6.2
Most Commonly Used Vaccinations Organized by Type of Vaccine and
Ranked Low Risk (Considered Safe) to High Risk (Not Recommended)
Vaccine Type Use in People With Multiple Sclerosis
Injectable seasonal
flu vaccine
Inactivated Considered safe
Hepatitis B vaccine Inactivated Considered safe
Pneumovax 23 and
Prevnar 13
pneumococcal
vaccines
Inactivated Considered safe
Tetanus vaccine Inactivated Considered safe; may reduce relapses
Gardasil human
papillomavirus
vaccine (HPV)
Inactivated Probably safe
Polio
Inactivated
(in most
countries)
Probably safe
Rabies Inactivated Probably safe; benefit likely outweighs
any risks
Measles-mumpsrubella vaccine
Live
attenuated
Probably safe in individuals not on
immunosuppressant medications
Varivax varicella
vaccines
Live
attenuated
Probably safe. Required before treatment
with fingolimod and alemtuzumab in
patients without previous exposure
Yellow fever
vaccine
Live
attenuated
May not be safe; should not be used by
individuals on immunosuppressant
medications
Shingrix vaccine Recombinant Considered safe
During Relapses
According to the Immunization Panel of the MS Council for
Clinical Practice Guidelines:
During relapses vaccination should be delayed until patients
have stabilized or have shown signs of improvement, usually 4
to 6 weeks after the start of the relapse. The exception being if
a patient required immediate tetanus vaccination.
Corticosteroid Use and Vaccinations
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Corticosteroid use could decrease the efficacy of a
vaccination, so it is advisable to wait usually 4 to 6 weeks
before administering the vaccine.27 This is because
corticosteroids are usually administered during the time of
relapse. Short-term use of glucocorticoids is usually not a
contraindication to receiving the vaccine or if doses <40 mg
are used.
23
Lemtrada (Alemtuzumab)
The recommendation is to vaccinate before treatment, 6
weeks before infusion. The live virus vaccine should not be
administered following a course of Lemtrada. There is no
specific recommendation regarding the administration of
inactivated vaccines following infusion.
A study showed that adequate antibody levels were produced
to seasonal flu vaccine and pneumococcal and meningococcal
vaccines.
Ocrevus
The Veloce study was done in the United States and Canada
evaluating the humoral response of Ocrevus to selected
vaccines. Vaccines studied were tetanus toxoid, pneumococcal
polysaccharide vaccine, seasonal influenza, 20-valent
pneumococcal conjugate vaccine, and keyhole limpet
hemocyanin. Ocrelizumab does deplete CD20+ B cells but
preserves the ability for B cells to reconstitute and preserves
preexisting humoral immunity. Humoral responses were
decreased at all time points in patients following ocrelizumab
use because of B cell depletion compared with controls.
Patients were, however, able to mount humoral responses to
the vaccines and neoantigen studied. Cellular immune
responses were not studied.
Live attenuated vaccines or live vaccines are not
recommended to be taken during treatment but can be given
up to 4 weeks before infusion. Findings from the Veloce study
confirm that all inactivated vaccines should be given at least
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2 weeks before the infusion. Flu vaccine is recommended
because a potentially protective humoral response is
generated, even if attenuated.29 No live attenuated or live virus
should be given during treatment or following treatment until
B cells have returned to normal levels.
Tecfidera
Live vaccines are not recommended. Immune response to
vaccines is maintained after Tecfidera exposure.60 Three
vaccine types were evaluated: tetanus/diphtheria toxoid to test
T cell–dependent recall response, pneumococcal vaccine
polyvalent to test T cell–independent humoral response, and
meningococcal oligosaccharide conjugate to test T cell–
dependent neoantigen response.
Gilenya (Fingolimod)
Humoral responses are decreased to influenza, pneumococcal
vaccine, and tetanus toxoid. That being said, administration of
flu vaccine is still recommended for patients. Avoid live
vaccines during treatment and for 2 months after treatment
discontinuation.
Tysabri (Natalizumab)
In the Natalizumab Safety and Efficacy in Relapsing
Remitting MS phase 3 clinical trial of Tysabri monotherapy in
relapsing MS, Tysabri 300 mg was administered versus
placebo and administered every 28 days for up to 116 weeks.
During this trial, 20% of patients received vaccinations. These
vaccinations included influenza, either polyvalent or
monovalent; hepatitis A; hepatitis B; typhoid; inactivated
polio; pneumococcal; tick-borne encephalitis; yellow fever;
diphtheria (Tysabri group only); diphtheria and tetanus;
tetanus antitoxin; tetanus toxoid; diphtheria, tetanus toxoids,
and pertussis (DTP); measles, mumps, rubella (Tysabri group
only); and live rubella vaccines (placebo group only). No
vaccine-related adverse events were reported in this trial other
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