Vaccine 32 (2014) 4730–4735

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Review

Efficacy of vaccination against influenza in patients with multiple sclerosis: The role of concomitant therapies Paolo Pellegrino a , Carla Carnovale a , Valentina Perrone a , Marco Pozzi b , Stefania Antoniazzi c , Sonia Radice a,∗ , Emilio Clementi b,d a Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital “Luigi Sacco”, Università di Milano, Via GB Grassi 74, 20157 Milan, Italy b Scientific Institute, IRCCS E. Medea, 23842 Bosisio Parini, Lecco, Italy c IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122, Italy d Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, University Hospital “Luigi Sacco”,*

a r t i c l e

i n f o

Article history: Received 14 April 2014 Received in revised form 6 June 2014 Accepted 12 June 2014 Available online 5 July 2014 Keywords: Multiple sclerosis Vaccine Efficacy Natalizumab

a b s t r a c t Multiple sclerosis is a chronic progressive demyelinating disease affecting over 2.1 million patients worldwide. Patients affected by MS are exposed to an increased risk of infection from communicable diseases, which may lead to severe disease relapses. Studies have analysed the issue of vaccination of MS-affected patients. These studies, however, deal mostly with safety-related issues documenting that most vaccines have been proven to be safe in MS patients and that vaccination is not associated with an increased risk of relapses. By contrast, evidence on the efficacy is comparatively scant and not yet systematised in a comprehensive picture. This aspect is however important, as both MS and its treatment alter the immune responses, a situation that may be associated with a reduced vaccine efficacy. We have now reviewed the literature and assessed the effects of the therapy for MS on vaccine efficacy; we focused on the vaccine against influenza as for the other vaccines the information is still too scant. The majority of drugs appear not associated with a reduced response to vaccination against influenza, with the notable exception of mitoxantrone and glatiramer acetate. For a few drugs, among which natalizumab, information is not sufficiently clear and additional studies are needed to draw a definite conclusion. These results highlight the importance to evaluate the efficacy of vaccination in patients treated with immunosuppressant drugs. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction Multiple sclerosis (MS) is a chronic progressive demyelinating disease of the central nervous system characterised by a complex array of symptoms that vary both over time and among individuals [1]. It affects over 2.1 million patients worldwide, has a heterogeneous course and is the second cause of disability among adults aged between 20 and 40 years [2]. In about 80–85% of the patients, MS initiates with a relapsing–remitting form(RRMS), characterised by a sequence of discrete exacerbations (relapse) and followed by partial or complete recoveries [3,4]. Other clinical manifestations such as the

∗ Corresponding author. Tel.: +39 0250319683; fax: +39 0250319682. E-mail address: [email protected] (S. Radice). http://dx.doi.org/10.1016/j.vaccine.2014.06.068 0264-410X/© 2014 Elsevier Ltd. All rights reserved.

progressive relapsing and the primary progressive MS may also occur with lower frequency and a higher disease severity. The introduction of a series of novel drugs has ameliorated impressively the therapy of multiple sclerosis over the last 20 years [5]. The first of these drugs has been beta-interferon (betaIFN) 1b approved in the United States (1993) and in Europe (1995) for relapsing–remitting MS (RRMS). Subsequently, nine other disease-modifying treatments (DMTs) have been approved in the USA including beta-IFN 1a (two formulations), glatiramer acetate (GA), mitoxantrone, natalizumab, fingolimod, teriflunomide and dimethyl fumarate (Table 1). As a side effect, however, these drugs may increase the susceptibility to infections of MS patients, because of their immune-suppressive/modulating mechanism of action [6]. In addition, infections increase the risk of relapses and these, at variance with the ones occurring in non infected patients, are more easily associated with neurological

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Table 1 Currently approved and under review multiple sclerosis disease-modifying therapeutics. Disease-modifying therapeutics

Year of approval

Available study of vaccine efficacy

Possible mechanism of interaction with vaccines

Interferon beta-1b

1993

Olberg 2014, Mehling 2013 and Schwid 2005

Interferon beta-1a (Avonex®) Glatiramer acetate Mitoxantrone Interferon beta-1a (Rebif®) Natalizumab Fingolimod

1996 1996 2000 2002 2006 2010

Olberg 2014, Mehling 2013 and Schwid 2005 Olberg 2014 Olberg 2014 Olberg 2014, Mehling 2013 and Schwid 2005 Olberg 2014 Mehling 2011

Teriflunomide Dimethyl fumarate

2012 2013

Bar-Or 2013 None

Alemtuzumab Laquinimod Daclizumab Ocrelizumab

Phase III Phase III Phase III Phase III

McCarthy 2013 None Extrapolated by other pathologies Extrapolated by other pathologies

Various including: Decreased INF-gamma production, inhibition of antigen presentation – Shift from Th1 towards Th2 cytokines Reduced proliferation of B- and T-lymphocytes – Blockade of the alpha-4 subunit of the VLA-4 receptor Binding to S-1-P preventing lymphocytes to exit lymph nodes Interference with lymphocytes proliferation Enhancement of endogenous mechanism(s) to counteract oxidative stress CD-52 antibody-dependent cellular cytolysis Inhibition of antigen presentation to T cells Increases in CD-56 bright NK cells CD-20 antibody-dependent B cell cytolysis

sequelae [7,8]. Vaccination represents therefore a mainstay in the prevention of communicable infectious diseases among patients with MS [6]. Vaccination, however, in MS as in many other diseases, raises concerns of safety and efficacy [9–13]. Single case reports or small case series raised safety concerns on the risk of MS relapses or early disease onset following vaccination [1,6,7]. Further analyses, however, did not confirm such a relationship [14–16], indicating an overall safety of most of vaccinations in MS patients [6]. Little information instead exists on the effects of drugs in MS patients, on the vaccination efficacy, i.e. the prevention of illness among vaccinated persons enrolled in controlled clinical trials, and effectiveness, i.e. the prevention of illness in the “real world” vaccinated population. This aspect is of relevance because several of the newly appeared drugs may interfere with the efficacy of vaccination, thus enhancing the risk of incurrence of vaccine preventable infections. In the large majority of the studies dealing with this topic, efficacy is measured by serologic conversion/response, which is thought to correlate well with immunity at the population level. In this analysis we have reviewed the available literature and provide an updated analysis of the studies addressing the efficacy of vaccination in patients affected by MS and in therapy with the existing immune-modulating/suppressive drugs. This review is focused on the vaccination against influenza asfor the other types of vaccinations information is too scant.

2. Methods We searched on PUBMED up to 2013 using the terms: “Vaccine” and “Multiple sclerosis”. We refined the research further including beta-interferon, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide and dimethyl fumarate as search terms alongside “Vaccine” and “Influenza Vaccine”. In this analysis we considered only the trivalent inactive influenza vaccine as live-virus vaccines are not recommended for people with MS. We carried out an initial screening by reading each abstract to identify the articles meeting these inclusion criteria, which were conclusively assessed after a thorough analysis of their content. The retrieved studies were then read in their entirety to assess appropriateness. The citations from each included articles were also examined, in order to identify any other published study potentially meeting inclusion criteria. We limited the research to the article written in English. As many of the drugs do not share a common mechanism of action, we explored the efficacy of vaccination in each of them separately. We do not report data on corticosteroids, although immune suppressant is widely used in MS [17], due to lack of information on

vaccine response in MS patients and the fact that in other settings they do not have an impact on vaccination [6,18]. Efficacy responses to vaccines may be measured with several tests; we choose in the majority of the cases the ones suggested by the EMA guidelines. We specify in the text when alternative correlates of immune protection were considered. 3. Influenza disease in MS patients Influenza is a disease of particular concern for patients affected by MS. Influenza epidemics cause illness in about 5–20% of the United States population every year with a yearly toll of approximately 300,000 hospitalisations and 36,000 deaths [19]. Patients affected by MS appear at higher risk of influenza-related hospitalisations, with an increased relative risk of 3.57 (CI 95% 3.06–4.15), as estimated by Montgomery et al. in a Swedish cohort of more than 20,000 patients and 200,000 controls [20]. The risk of infectionassociated mortality in the same cohorts was estimated to be 5.19 (CI 95% 4.90–5.50). In Fig. 1, we report the analysis we carried out on the monthly mortality for MS in the United States compared with the number of MS patients who died for pneumonia or influenza. These data arise from the centres for disease control and prevention and highlight the burden of influenza among MS patients [21]. In RRMS patients influenza infection increases not only mortality and hospitalisation, but also the risk of relapse episodes [22]. This observation arises from a study of De Keyser et al. who evaluated the effects of influenza infection in patients with RRMS and found that 33% of 36 infected patients developed an acute relapse [22]. 3.1. Vaccination and untreated patients The efficacy in untreated MS patients was evaluated in three studies [23–25]. Miller et al. carried out a placebo-controlled trial in the autumn of 1993 [24], enrolling 104 patients who received the influenza vaccine or the placebo. Patients were followed for 6 months and neurological status and occurrence of influenza assessed. Forty-nine patients received influenza vaccine and 54 received placebo but no significant difference was observed between the two groups in terms of number of patients experiencing an influenza-like illness [24]. Several reasons, such as the occurrence of pathologies caused by other pathogens, or vaccine attenuated influenza disease, may explain the absence of reduction of influenza-like illness observed among vaccinated patients. The presence of these biases in effectiveness indicates the necessity of assessing serologic and cellular responses to vaccine which are the most reliable markers of protection to natural influenza infection [25]. Indeed, in a subsequent study, based on the humoural

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600

160

140

500

400

MS plus Pneumonia

120

Only MS

100

300

80

60

200

40 100

20

MS plus Pneumonia Jan., 1999 May, 1999 Sep., 1999 Jan., 2000 May, 2000 Sep., 2000 Jan., 2001 May, 2001 Sep., 2001 Jan., 2002 May, 2002 Sep., 2002 Jan., 2003 May, 2003 Sep., 2003 Jan., 2004 May, 2004 Sep., 2004 Jan., 2005 May, 2005 Sep., 2005 Jan., 2006 May, 2006 Sep., 2006 Jan., 2007 May, 2007 Sep., 2007 Jan., 2008 May, 2008 Sep., 2008 Jan., 2009 May, 2009 Sep., 2009 Jan., 2010 May, 2010 Sep., 2010

0

Only MS

0

Fig. 1. Comparison between the monthly number of deaths for Multiple Sclerosis (only MS) and for pneumonia among Multiple Sclerosis patients (MS plus pneumonia).

response to the influenza vaccine, Moriabadi et al. found no differences between a group of12 patients with MS and a group of 28 controls [25].These results indicate that the influenza vaccine is effective in MS untreated patients. 3.2. Vaccination and disease-modifying drugs 3.2.1. Beta-interferon As summarised in Tables 1 and 2, the largest number of studies was conducted in patients treated with beta-interferon. The efficacy of influenza vaccination in patients affected by MS and treated with beta-interferon was assessed in three studies comparing the immune response in different subjects and for different vaccines. Two of these studies were conducted comparing MS patients and healthy controls [26,27], while the third examined differences between treated and untreated MS patients [28]. Pooled together, these studies compared influenza vaccine efficacy in over 200 MS patients treated with beta-interferon and 500 healthy or untreated MS controls. All these studies concurred in indicating a comparable efficacy of the influenza vaccine between MS patients treated with beta-interferon and healthy controls [26–28]. A recent study, albeit in the mouse model, shows that betainterferon is protective against influenza A virus infection [29]. Taken together, these data indicate an overall efficacy of seasonal influenza in patients treated with beta-interferon. 3.3. Glatiramer acetate Glatiramer acetate represents an established and effective treatment, in clinical practice from over two decades [5]. Glatiramer acetate is composed of a synthetic four-amino acid copolymer that simulates myelin basic protein and its administration results in a shift from Th1 towards Th2 cytokines, which may contribute to disease amelioration [5]. Available data on influenza vaccine efficacy in patients with MS are scant, with only one study carried out to explore this issue

[26]. This study found that the number of patients with persistent protective HI titres was lower in patients treated with GA than in healthy controls for H1N1 vaccination in 2009 (21.6% vs 43.5%), H1N1 vaccination in 2010 (58.3% vs 71.2%) and for H3N2 vaccination in 2010 (41.7% vs 79.5%). These data indicate that, among MS patients treated with glatiramer acetate, the influenza vaccine may determine a grade of protection lower than in healthy individuals. 3.4. Mitoxantrone Mitoxantrone is an anthracenedione chemotherapeutic agent that inhibits T-cell activation and reduces proliferation of B- and T cells [5]. Olberg et al. assessed the efficacy of influenza vaccine in patients treated with this drug [26]. They found that none of the mitoxantrone-treated patients was protected by the H1N1 2009 vaccination (0/11 vs 94/216 healthy control). Similarly, only one patient had a detectable titre for H1N1 and H3N22010 vaccination (1/4 vs 58/73 healthy control). Despite these results being preliminary and requiring further validation, they indicate that mitoxantrone can interfere with influenza vaccine efficacy. In this respect, it would be important to define also the effect of timing on the immune response, as the drug is administered every 3 months. 3.5. Natalizumab Natalizumab was the first targeted agent approved for the treatment of RRMS [30]. This drug targets the alpha-4 subunit of the VLA-4 receptor expressed on activated T cells and other mononuclear white blood cells. VLA-4 interacts with the vascular cell adhesion molecule 1 on endothelium and fibronectin in tissue; by blocking VLA-4 it prevents inflammatory cell migration from the vasculature and towards the CNS [5,30]. The efficacy of influenza vaccine in patients treated with natalizumab was evaluated in two studies, both comparing MS patients and healthy controls [26,31]. These explorative studies yielded conflicting results, one reporting a lower rate of protection in patients treated with natalizuamb (23.5% vs 43.5%; [26]), the other

– – – – See text – – – – – – – – – See text – NSC: No significant change; GA: Glatiramer Acetate; NTZ: Natalizumab; MTX: Mitoxantrone; FGL: Fingolimod; INF-B: Interferon Beta; TRF: Teriflunomide; D: Drug recipients; C: Controls

FGL

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no significant differences [31].These conflicting results may be attributed to the relative small sample size of these studies. Further analyses are therefore required to solve this issue.

44 88 88 100 – – – 93

INF-B (%) MTX (%)

0 25 25 – – – – – 23 50 75 – – 56 – –

NTZ (%) GA (%)

22 42 58 – – – – – HIA HIA HIA ELISA (IgG, IgM), ELIspot HIA, GMT, SR ELISA (IgG) ELISA (IgG, IgM), ELIspot HIA

Method

D: 45.5 (11.0)/C: 41.1 (12.0) D: 50.6 (9.8)/C: 42.8 (13.3) D: 50.6 (9.8)/C: 42.8 (13.3) D: 40 (29–49)/C: 38 (19–46) D: 46.1 (8) AND 43.7 (8.6)/C:45.3 (11) D: 39 (20 - 56)/C: 29 (20 - 42) D: 44 (31 - 60)/C: 37 (19 - 46) D: 41.6 (8.3)/C: 43 (7.9) Olberg 2014 (cohort 2009 H1N1) Olberg 2014 (cohort 2010 H3N2) Olberg 2014 (cohort 2010 H1N1) Mehling 2013 Bar-Or 2013 Vågberg 2012 Mehling 2011 Schwid 2005

Female % Age Study

Table 2 Influenza vaccine; post vaccine comparison.

D: 66.4/C:75.9 D: 69.4/C:76.6 D: 69.4/C:76.6 D: 84.6/C: 60.6 D: 67.5 AND 69.2/C:67.4 D: 82.3/C: 50 D: 57.1/C: 33.3 D: 83.7/C: 76.6

TRF

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3.5.1. The oral disease-modifying medications Fingolimod was the first oral DMT for relapsing MS to be approved by the Food and Drug Administration (FDA) (2010) and the European Medicines Agency (EMA) (2011) [5]. T-lymphocytes normally exit lymph nodes along an S-1-P concentration gradient, which directs them back into the blood. Fingolimod binds to S-1-P receptors on naïve and activated Tlymphocytes, leaving them temporarily unable to respond to the S-1-P signal. Thus, in MS, fingolimod is believed to act by retaining autoreactive lymphocytes in lymph nodes, away from the CNS where they incite inflammation and tissue damage [5]. Preclinical data indicate that treatment with fingolimod does not result in deviations from the natural pattern of viral control in simian human immunodeficiency virus (SHIV)-infected rhesus macaques [32], nor has any effect on the disease course and T cell exhaustion in mice infected with lymphocytic choriomeningitis virus [33]. However, treatment with fingolimod led to a significant reduction of influenza-antigen specific CD8+ T cells in lungs of animals infected with influenza [34]. In a recent analysis, Mehling et al. compared the influenza vaccine efficacy between a group of 18 healthy controls and a group of 14 MS patients treated with fingolimod [35].They found that fingolimod-treated patients may mount a vaccine-specific adaptive immune response which is comparable to the response observed in healthy control [35]. In a similar analysis, Boulton et al. compared T-cell dependent and independent responses to the neoantigens in healthy volunteers treated with fingolimod [36]. The authors found that responder rates were identical between the placebo and the 0.5mg fingolimod groups for anti-keyhole limpet haemocyanin IgG (both >90%) and comparable for the anti-pneumococcal polysaccharides vaccine 23 IgG (55% and 41%, respectively). Fingolimod did not affect anti-tetanus toxoid immunogenicity, and delayedtype hypersensitivity response did not differ between the placebo and the 0.5-mg fingolimod groups [36]. Taken together these observations indicate that the efficacy response to the influenza vaccine is not impaired by fingolimod treatment. Teriflunomide is the active metabolite of leflunomide, which has been approved in the USA since 1998 to treat rheumatoid arthritis. It can be administered at a daily dose of either 7 or 14 mg and inhibits the enzyme dihydroorotate dehydrogenase, thus reducing the abnormally high levels of stimulated lymphocyte proliferation observed in MS patients [5]. As teriflunomide does not kill resting lymphocytes, previously acquired cellular immunity is preserved during treatment [5]. Up to date, only one study, the Teriflunomideand Vaccination (TERIVA) has analysed the effect of this drug on influenza vaccine efficacy. The TERIVA study was a multicentre, multinational, parallel-group study involving 128 patients in three treatment groups receiving teriflunomide 7 mg or 14 mg once daily, or IFN-␤-1 [37]. The results of the TERIVA studies demonstrate that patients treated with teriflunomide are able to mount effective immune responses to seasonal influenza vaccination. Although the response to all vaccine strains in all treatment groups was sufficient for vaccination to be considered protective, there was a slightly diminished response in the group treated with 14-mg daily [37]. 3.6. Monoclonal antibodies Alemtuzumab is a monoclonal antibody directed against the CD52 antigen, a surface glycoprotein of unknown function

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expressed on all mature B and T-lymphocytes, but not on haematological precursors [5,38]. Treatment causes antibody-dependent cell-mediated lysis, producing a profound lymphopoenia from which B-cells rapidly recover, whereas CD4+ T-helper cells take up to 5 years to reach pretreatment levels [5,38]. An assessment of the efficacy of influenza vaccine in patients treated with alemtuzumab has not yet been reported, and the available information is on other vaccines. In a recent analysis, McCarthy et al. explored immune-competence in 24 patients after treatment by measuring antibody responses to three vaccines (namely the vaccine against diphtheria, tetanus, and poliomyelitis; the conjugate one against Haemophilus influenzae type b and the meningococcus group C; and the anti-pneumococcal polysaccharide vaccine) [39]. In this pilot case-control study, the authors compared their observation with well-defined historical controls and found that the responses to the vaccines were normal [39]. Rituximab, a chimeric anti-CD20 antibody and ocrelizumab, which is its follow-up fully humanised counterpart, deplete Blymphocytes by cell lysis [5]. Up to date, no results from studies addressing the efficacy or the effectiveness of the influenza vaccine in MS patients treated with these drugs have been reported. However, the effect of these monoclonal antibodies on vaccine response may be extrapolated from other diseases [6]. In particular, lymphoma patients treated with rituximab were unable to develop protective antibodies against the influenza vaccine [40,41]. Likewise, the humoural response was impaired in patients with rheumatoid arthritis [42,43], while the cell-mediated response remained intact [44]. Daclizumab is a humanised monoclonal antibody directed against the alpha subunit of the IL-2 receptor, formerly approved to limit rejection of kidney transplants [5]. While no information is available on the effect of daclizumab on vaccine in MS patients, some data are available from analyses on transplanted patients; they indicate a progressive decline in pneumococcal polysaccharide antibody titre in patients receiving daclizumab and the triple immunosuppression therapy [45]. Further analyses are nevertheless required to assess conclusively the efficacy of this drug.

4. Conclusions and future research direction Vaccination impacts on patients afflicted by MS depending on their therapeutic regimen. Untreated patients or patients in treatment with interferon beta appear capable of mounting a normal vaccine response. Likewise, patients treated with fingolimod, teriflunamide and alentuzumab may be able to mount a proper response to vaccination. These results, however, require further validation, as they arise from single or few studies. Likewise, the analysis of data on natalizumab did not yield concordant evidence about the efficacy of vaccination in patients treated with this drug, and analyses on larger samples are needed to confirm this datum. Patients in treatment with mitoxantrone and glatiramer acetate appear to have a poor response to the vaccine against influenza and this may suggest the opportunity of a second dose of vaccine; further studies are however required to assess the real clinical benefit of this option. For other drugs, such as rituximab or daclizumab, there is not sufficient evidence from patients affected by MS. The extension of results from other pathological setting warns about a possible lower response to vaccination. These observations, however, deserve to be confirmed by specific analyses in the MS setting. As vaccination against influenza may not be efficacious in some MS patients under treatment with some of the above mentioned drugs and extensive studies on this topic are still lacking, clinician should consider the possibility of assessing the efficacy response to

the influenza vaccine in these high-risk patients. This assessment should be carried out four weeks after vaccine administration [6]. A limit of our review is that we included only studies analysing efficacy of vaccination, and not the influenza incidence among vaccinated patients. This represents an important issue as serological markers in immunocompromised individuals may not be an accurate biomarker of efficacy. It has to be noted that in a study in which incidence of influenza and efficacy of vaccination were both studied in the same population no differences were observed. Interestingly in this study incidence of influenza disease in the vaccinated population was of 12% [27]. In our analysis, we retrieved studies dealing mainly with influenza and pneumococcal vaccines. However, recent case series, studies and guidelines yielded attention to other communicable diseases such as Varicella zoster, which should be considered for specific DMD such as fingolimod. In this view, studies on the efficacy and safety of Varicella zoster vaccine in MS patients should be undertaken. Funding The financial support by the Italian Medicines Agency, AIFA, and the Italian Ministry of Health (RC 2014 to EC) is gratefully acknowledged. Competing interests None declared. References [1] Oreja-Guevara C, Wiendl H, Kieseier BC, Airas L, for the NeuroNet Study Group. Specific aspects of modern life for people with multiple sclerosis: considerations for the practitioner. Ther Adv Neurol Disord 2014;7:137–49. [2] National Multiple Sclerosis Society; 2013. http://www.nationalmssocietyorg/about-multiple-sclerosis/what-weknow-about-ms/faqs-about-ms/indexaspx. [3] Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502–17. [4] Lassmann H, Brück W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol 2007;17:210–8. [5] Cross AH, Naismith RT. Established and novel disease-modifying treatments in multiple sclerosis. J Intern Med 2014, http://dx.doi.org/10.1111/joim.12203 [Epub ahead of print]. [6] Loebermann M, Winkelmann A, Hartung HP, Hengel H, Reisinger EC, Zettl UK. Vaccination against infection in patients with multiple sclerosis. Nat Rev Neurol 2012;8:143–51. [7] Correale J, Fiol M, Gilmore W. The risk of relapses in multiple sclerosis during systemic infections. Neurology 2006;67:652–9. [8] Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med 2001;344:319–26. [9] Pellegrino P, Carnovale C, Perrone V, Salvati D, Gentili M, Brusadelli T, et al. On the association between human papillomavirus vaccine and primary ovarian failure. Am J Reprod Immunol 2014;71:293–4, http://dx.doi.org/10.1111/aji.12190. Epub 2013 Dec 23. [10] Pellegrino P, Carnovale C, Perrone V, Salvati D, Gentili M, Antoniazzi S, et al. Human papillomavirus vaccine in patients with lupus erythematosus. Epidemiology 2014;25:155–6, systemic http://dx.doi.org/10.1097/EDE.0000000000000033. [11] Pellegrino P, Carnovale C, Perrone V, Pozzi M, Antoniazzi S, Clementi E, et al. Acute disseminated encephalomyelitis onset: evaluation based on vaccine adverse events reporting systems. PLoS One 2013;8:e77766, http://dx.doi.org/10.1371/journal.pone.0077766, eCollection 2013. [12] Pellegrino P, Carnovale C, Perrone V, Antoniazzi S, Pozzi S, Clementi E, et al. Can HPV immunisation cause ADEM? Two case reports and literature review. Mult Scler 2013 [Epub ahead of print]. [13] Pellegrino P, Carnovale C, Borsadoli C, Danini T, Speziali A, Perrone V, et al. Two cases of hallucination in elderly patients due to a probable interaction between flu immunization and tramadol. Eur J Clin Pharmacol 2013;69:1615–6. [14] DeStefano F, Verstraeten T, Jackson LA, Okoro CA, Benson P, Black SB, et al. Vaccine safety Datalink research group, national immunization program, centers for disease control and prevention. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol 2003;60: 504–9. [15] Pellegrino P, Carnovale C, Pozzi M, Antoniazzi S, Perrone V, Salvati D, et al. On the relationship between human papilloma virus vaccine and autoimmune

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