The different available treatments for MS influence the immune system in distinct ways and,
therefore, may lead to specific infectious risks. Whereas immunomodulating therapies have no
impact on infection risks [Cahill 2010; Winkelmann 2016], the most recent drugs with
immunosuppressant activity could increase persons with MS' vulnerability to infections
[Löbermann 2012; Olsson 2014]. MS patients are routinely screened for latent or active
infections before starting any disease modifying drugs (DMDs). Specific infectious agents
should be evaluated for each second line [Williamson 2015, Yang 2014, Kohlmann 2015]. Another
cause of increased susceptibility to infections in MS patients is disability: patients have a
greater risk for serious and fatal infections due to MS-related functional limitations as
pulmonary problems and bladder and bowel dysfunctions [Montgomery 2013; Nelson 2015]. In
addition, there is consistent evidence that exacerbations could be a consequence of
infectious diseases, such as bacterial infections of urinary tract, viral respiratory
diseases or gastroenteritis, with a two-fold increase in risk of relapse after infection
[Panitch 1994; Rutschmann 2002; Loebermann 2012; Williamson 2015]. In such case, the
mechanisms underlying relapses are not fully understood [Steelman 2015], but probably
molecular mimicry and bystander activation play a role in this process [Loebermann 2012].
Therefore, it is important to promote any prevention strategy that may reduce the risk of
acquiring infections, such as vaccination.
Vaccination is the main proven tool for primary prevention of serious, and sometimes
life-threatening diseases and one of the most cost-effective public health measures
available.
There are 4 main types of vaccines: live-attenuated vaccines, inactivated vaccines,
subunit/recombinant/polysaccharide/conjugate vaccines and toxoid vaccines. Live vaccines are
made using an attenuated or weakened form of the pathogen. These vaccines have a high
efficacy but, containing a live pathogen, they have a potential risk of infection,
particularly in patients with a natural or acquired immunodeficiency. Further, concerns about
live vaccines administration to close family members of patients have been raised, as there
could be the risk that immunised individual release the live pathogens [Williamson 2016]. On
the contrary, the other types of vaccines can be safely used by persons with an impaired
immune system [www.vaccines.gov].
In Italy, before 2017, 4 vaccinations were mandatory for children (against diphtheria from
1939, polio from 1966, tetanus from 1968 and hepatitis B from 1991), whereas several others
were only recommended. Due to inadequate immunisation coverage, the obligation was recently
extended to 10 vaccines, adding the ones against Haemophilus influenzae type B, pertussis,
measles, mumps, rubella and varicella for newborns. In addition, there are other recommended
vaccines at different ages, i.e. vaccination against rotavirus, meningitis B and C,
pneumococcal disease in childhood, against human papilloma virus in adolescents, and against
tetanus, diphtheria, pertussis, influenza, pneumococcal disease and herpes zoster for those
aged 65 years and older [www.salute.gov.it].
In MS population, there are some concerns about the utilization of vaccines. It is unclear
(at least for some vaccines) whether vaccinations may trigger the disease or increase the
risk of relapse due to the stimulation of the immune system, as the infections themselves
[Loebermann 2012]. The vaccines against hepatitis B virus, tetanus, tick-borne encephalitis,
H1N1 virus and seasonal influenza are considered safe, even if small groups of patients (with
a very active form of MS) report an increased risk of relapse after influenza or H1N1 vaccine
[Loebermann 2012]. An increased risk of relapses was reported also after yellow-fever
immunisation in a single study conducted in a very small cohort of RR-MS patients [Farez
2011b]. On the other hand, a protective role is reported for some vaccines, for example for
bacillus Calmette-Guérin vaccine, and for vaccines against tetanus and diphtheria [Loebermann
2012]. For all other vaccines, no data are available [Mailand 2017].
Moreover, specific DMDs may increase the risk of infectious complications from vaccines
composed by live attenuated microorganism [MSC for clinical practice guidelines]. Live
attenuated vaccines are considered safe for patients receiving an immunomodulator agent such
as glatiramer acetate or interferon, but there are relatively few data on the safety of these
vaccines for the more recently approved immunosuppressant agents. Hence, patients treated
with these drugs should avoid live attenuated vaccines during the treatment and for a period
of 3 months after discontinuation of treatment [Cahill 2010; Oreja-Guevara 2014]. In
addition, MS patients experiencing a serious relapse should delay the vaccination until 4-6
weeks after the exacerbation [National MS society].
Finally, DMDs could reduce the efficacy of vaccination leaving people susceptible to
diseases, however the published studies showed conflicting results [Williamson 2016].
Several new drugs have been developed to treat multiple sclerosis (MS) in the last 2 decades.
Balancing benefit and risk in recent MS treatment management is decisive. In the era of
disease modifying drugs (DMDs), that alter immune function, the reactivation or de novo
acquisition of infectious diseases is gaining great relevance. The understanding of the
potential adverse effects of these immunological active therapies is a key part of the
decision-making process when weighting different treatment options. Consequently, prior to
starting an immunosuppressant treatment, it is necessary to know the immunisation status of
patients, including immunity elicited both by natural infections and vaccinations. The
knowledge of susceptibility to infections of patients is recommended for therapeutic choice.
First of all, it is mandatory for some immunosuppressant drugs, or suggested for others, to
assess the immunisation status against herpes zoster virus, because the reactivation of this
disease might be serious. Vaccinations against varicella and herpes zoster contain the
live-attenuated virus, so immunocompromised patients should not be immunised with these
vaccines [Williamson 2016]. For the same reason, the immunisation against measles, mumps and
rubella could be recommended in susceptible subjects because these pathogens could trigger
serious complications, such as encephalitis and pneumonia. Therefore, in patients who have
never had natural infections, it could be necessary to take into account immunisation with
these live-attenuated vaccines just early after MS diagnosis, in view of a possible future
treatment with an immunosuppressant drug.
In addition, there are other vaccines against other frequent infectious agents which are
recommended for general population and for groups at risk: tetanus, diphtheria and pertussis
(which require a booster dose every 10 years for all persons), seasonal influenza,
pneumococcal, meningococcal, Haemophilus influenzae type B (Hib), hepatitis A and B virus.
According to the international public health recommendations, all individuals in the older
age groups (usually over 65 years of age) and those from age of 6 months with a chronic
disease with increased risk for severe outcomes of influenza complications, must be
vaccinated every year. The medical conditions that could represent a risk factor for
influenza complications include any situation compromising respiratory functions, as in many
neurological disorders, and the immunosuppression due to disease or treatment
[www.ecdc.europa.eu]. For the same reasons, the pneumococcal vaccine is recommended because,
in susceptible people, flu virus may trigger an infection by Streptococcus pneumoniae
[www.cdc.gov]. Regarding Hib, individuals with a secondary immunodeficiency may be at risk of
developing invasive disease if exposed to the pathogen [Nix 2012]. In case of outbreak of
meningococcal or hepatitis A, or in case of risk of hepatitis B, adults might be vaccinated
[www.ecdc.europa.eu].
Another aspect to take into account is the presence of hepatitis B chronic infections, as the
immunosuppressant treatment must be preceded and accompanied by a specific antiretroviral
drug blocking the viral DNA synthesis [Orlicka 2013].
The positive effect on individual well being is coupled with a favourable economic impact in
public health. Also in patients with MS, vaccination could reduce the disease burden and
consequently the social cost, as it might reduce eventual relapses or other severe
complications [Rutschmann 2002]. Therefore, the knowledge of the immunisation status could
help policy makers and program strategies to assess the need of a vaccine campaign targeted
to MS patients.
Despite these considerations, there are no available data about the prevalence of patients
susceptible to infections, therefore unvaccinated or people never exposed to natural
infections. Concerning the severe and potentially life-threatening infective complications
associated with the immunosuppressant agents used to treat MS, the use of specific registries
and databases to collect and evaluate infection/vaccine safety data after drug approval is
advisable.
The safety of most vaccines in MS patients has been only partly investigated, so that a
correlation between vaccination and MS relapses has been hypothesized only for some vaccines.
However, these conclusions are based on few studies, mostly carried out on small study sample
sizes. The lack of large amounts of data regarding the vaccine safety in MS population
precludes the possibility to offer clear-cut recommendations.
The first aim of the study is to collect historical data on the immunisation status, due to
past exposure to natural infectious diseases or vaccines, in a large multicentric cohort of
MS patients with regards to the most frequent vaccine-preventable viral and bacterial
infections.
The second aim is to assess the potential role of vaccines used in adulthood in
determining/worsening MS inflammatory activity, as well in disease progression. In
particular, any vaccination against hepatitis A and B, measles, mumps, rubella, varicella,
diphtheria, pertussis, seasonal influenza, herpes zoster virus, meningococcal and
pneumococcal bacteria will be considered. In addition to these communicable diseases, the
tetanus vaccine will be included due to the high coverage of this vaccination. MS activity
and progression will be assessed evaluating the occurrence of relapse within 6 months from
vaccination and using the annual relapse rate and its trend during the study period.
STUDY DESIGN The project is a 3-year observational, retro- and prospective study. Aim 1:
Multicenter cross-sectional study on the immunisation status, due to past exposure to natural
infectious diseases or vaccines, will be conducted in a MS patient cohort. Sub-analyses will
be stratified by sex, patient's age at the time of enrolment, disease duration from clinical
onset, disability, current/past DMDs, geographic area of birth and residence, type of
vaccine, comorbidity with special regard to autoimmune/immune mediated and/or infectious
diseases. 25 MS Centers from Northern, Central and Southern Italy will represent the study
sites.
Aim 2: The potential role of vaccines used in adulthood in determining/worsening MS
inflammatory activity, as well on disease progression will be conducted by means of a
self-controlled case series study over the all MS cohort. A 'case' will be defined as
'exposed' if at least one confirmed relapse occurred during the risk period of 2 months and
during the extended risk period of 6 months after vaccine administration; and not exposed
otherwise [Galeotti 2013].
