Clinical trial NCT04300868: Immunisation Status and Safety of Vaccines in Italian MS Patients
Official title: Immunisation Status Against Major Communicable Diseases Preventable With Vaccines, and Safety of Vaccines, in a Cohort of MS Patients. An Italian Multicenter Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Multiple Sclerosis
Keywords: immunisation status
vaccine safety
vaccination
Lead sponsor: University of Siena
Sponsor class: OTHER
Collaborators: name: Fondazione Italiana Sclerosi Multipla
name: San Luigi Gonzaga Hospital
name: University of Roma La Sapienza
name: Universita degli Studi di Catania
name: Universita degli Studi di Genova
name: San Camillo Hospital, Rome
name: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
name: University of Florence
name: Istituto Neurologico Mediterraneo Neuromed S. R. L
name: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
name: Maggiore Bellaria Hospital, Bologna
name: Federico II University
name: Ospedale San Donato
name: Ospedale San Giuseppe di Empoli
name: Ospedale Livorno
name: Ospedale Misericordia e Dolce
name: Ospedale della Misericordia
name: Ospedale San Jacopo
name: Ospedale Felice Lotti di Pontedera
name: Campus Bio-Medico University
name: Università degli Studi di Ferrara
First posted: 2020-03-09
Enrollment: 3000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Relapsing remitting (RR)-MS patients consecutively diagnosed from January 2011 to December 2020 will be enrolled in the study upon informed written consent. The choice of January 2011 is suggested by the need to apply the 2010 Polman's diagnostic criteria for MS \[Polman 2011\] in order to ensure most homogeneous diagnoses across patients.

Both for retrospective and prospective phase, each Center will identify, through clinical records, newly diagnosed MS patients in the considered period and consistently followed in the Center, and the enrolment will be made during routine ambulatory visits.

Brief summary: Multiple sclerosis (MS) patients are more susceptible to infections than the general population in relation to some specific therapies or increasing disability. Clearly, the use of immuno-suppressant/modulatory drugs requires particular attention to the occurrence of infectious events. In this perspective, among still unmet clinical needs in MS patients is a comprehensive picture on the immunisation status against infectious diseases, especially those preventable with vaccines. Despite of the relevance of vaccinations, there are still some concerns about their utilization in MS patients. In literature, results about their safety are conflicting or incomplete and it is yet unclear if some vaccines may trigger MS relapses.

GOALS: 1) to assess immunisation status, due to past exposure to natural infectious diseases or vaccines, against major infectious agents preventable by available vaccines; 2) to assess the safety of most utilized vaccines in the clinical practice by recording relapses as adverse event in the considered risk period after vaccination.

The 3-year project is conceived as a multicenter, observational, both retro- and prospective study. A cohort of about 3,000 MS subjects will be enrolled among databases of 25 clinical Centers in Italy. All patients diagnosed with relapsing remitting (RR) MS according to the 2010 Polman's criteria from 01/2011 to 12/2020 will be enrolled. Available data on natural immunisation will be collected from the historical clinical records of Centers, taking into account the presence of specific serum antibodies, whereas available data on vaccinations will be collected from vaccination records.

To study the impact of vaccines on the risk of relapse, data about patients receiving a vaccination during the disease will be analysed. The study follow-up period will be between 2 and up to 6 months following vaccination: the 2-month period is considered as the maximum clinical risk, whereas 6 months as the maximal extension of risk in time. In addition, in the case of a clinical relapse, the variation of disability will be evaluated with EDSS scale confirmed at 6 months. These data might shed light on the relationship between vaccination and MS, adding new insights on their safety.

The knowledge of the immunisation status is crucial for the clinical practice in the management of the new disease modifying drugs (DMDs), and for the public health to establish the possible need of a vaccine campaign targeted to MS patients.

Detailed description: 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 \[Galeotti 2013\].

Eligibility criteria: Inclusion Criteria:

* diagnosis of RR-MS according to the 2010 Polman's diagnostic criteria \[Polman 2011\] or the 2017 revision of the McDonald criteria for the prospective cohort \[Thompson 2018\]
* written informed consent must be obtained before the enrolment

Exclusion Criteria:

* clinically isolated syndrome (CIS) and progressive MS forms
* unavailability or unreliability of medical records

Primary outcomes:
measure: prevalence of MS patients susceptible to infections
timeFrame: december 2021
Secondary outcomes:
measure: safety of vaccination in MS patients
timeFrame: december 2021
Other outcomes:
Locations:
city: Siena
country: Italy
facility: university of Siena
state: SI
Study officials:
affiliation: University of Siena
name: Monica Ulivelli, researcher
role: PRINCIPAL_INVESTIGATOR
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