Journal of Neurology

, Volume 258, Issue 7, pp 1197–1206

Immunizations and risk of multiple sclerosis: systematic review and meta-analysis

Authors

  • Mauricio F. Farez
    • Department of NeurologyDr Raúl Carrea Institute for Neurological Research, FLENI
    • Department of NeurologyDr Raúl Carrea Institute for Neurological Research, FLENI
Review

DOI: 10.1007/s00415-011-5984-2

Cite this article as:
Farez, M.F. & Correale, J. J Neurol (2011) 258: 1197. doi:10.1007/s00415-011-5984-2

Abstract

The role of vaccinations in risk of developing multiple sclerosis (MS) or in risk of relapse has not been well established. The aim of this study was to estimate the effect of immunizations on risk of developing MS in adults as well as in subsequent risk of relapse. Systematic search for publications in MEDLINE (1966–January 2011), EMBASE (1977–January 2011) and the Cochrane Central Register of Controlled Trials (CENTRAL) (1961–January 2011). Both randomized clinical trials and non-randomized studies addressing the effect of any Center for Diseases Control (CDC) recommended vaccine for children, adults or travelers and BCG on risk of MS or disease relapse were included. Two reviewers independently extracted information from articles selected using a predefined datasheet. No significant change in the risk of developing MS after vaccination was found for BCG (OR 0.96, 95% CI 0.69–1.34), Hepatitis B (OR 1.00, 95% CI 0.74–1.37), Influenza (OR 0.97, 95% CI 0.77–1.23), Measles–Mumps–Rubella (MMR) (OR 1.02, 95% CI 0.64–1.61), Polio (OR 0.87, 95% CI 0.61–1.25) and Typhoid fever (OR 1.05, 95% CI 0.72–1.53). We found decreased risk of developing MS for Diphtheria (OR 0.60, 95% CI 0.40–0.90) and Tetanus (OR 0.68, 95% CI 0.54–0.84). Influenza immunization was also associated with no change in risk of MS relapse (RR 1.24, 95% CI 0.89–1.72). Risk of developing multiple sclerosis remained unchanged after BCG, Hepatitis B, Influenza, MMR, Polio and Typhoid fever immunization, whereas diphtheria and tetanus vaccination may be associated with a decreased risk of MS. Further research is needed for the remaining vaccines.

Keywords

Multiple sclerosisSystematic reviewMeta-analysisVaccines

Introduction

Widespread use of immunizations has been one of the most successful measures adopted in public health [1]. Despite the overwhelming benefits reported for most vaccines, concerns are raised from time to time linking immunizations to different conditions such as autism [2] and autoimmune disorders [3] such as multiple sclerosis (MS) [4]. Unfortunately, in many cases, these studies are merely case reports, poorly designed observational studies, or well-designed studies with a small number of participants from which valid conclusions cannot be drawn. Thus, establishing positive, negative or lack of association between the risk of developing MS or an exacerbation of the disease with any vaccine currently in use has been elusive.

The purpose of this study was to systematically review all randomized clinical trials (RCTs) and non-randomized studies (NRS) reporting on risk of developing MS, or a relapse, following any immunization recommended by the CDC for use in children, adults, or travelers, and also BCG.

The need of a systematic review on the role of vaccinations in MS providing doctors and patients with a clear reference source on the subject was the main objective of this paper, as well as to encourage future well-designed studies investigating how specific immunizations affect MS patients in particular.

Methods

A detailed method protocol was specified and documented in advance by both authors. This review was prepared following the PRISMA statement guidelines [5] for systematic reviews and meta-analyses (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) (see Supplementary Material for the PRISMA checklist). Even though we expected the number of NRS to be greater than the number of RCTs, we chose PRISMA guidelines over MOOSE guidelines (Meta-Analysis of Observational Studies in Epidemiology) because we considered them to be more updated and better suited to both NRS and RCTs. A detailed description of the methods is provided as supplementary material (Appendix 1).

We systematically searched MEDLINE (1966–January 2011), EMBASE (1977–January 2011) and the Cochrane Central Register of Controlled Trials (CENTRAL) (1961–January 2011) for randomized controlled trials and non-randomized studies examining the effect of immunizations in the risk of MS and the risk of relapse in adult MS, in English and in other languages. In addition, we hand searched abstracts of selected conferences from 2005 to 2011, including AAN, EFNS, ENS, and ECTRIMS. References from relevant studies and previous reviews were also searched.

Non-randomized studies and randomized clinical trials written in English or in other languages, describing the effect of immunizations on risk of developing MS or risk of disease relapse were included. Case reports and case report series were excluded. All immunizations recommended by the CDC [6] for use in children, adults or travelers were analyzed, and BCG was added to the list.

In duplicate and independently the two authors screened all the studies and selected the articles that satisfied the eligibility criteria. The data was extracted onto a standardized data extraction sheet by one of the authors (MFF) and checked independently by the second author (JC). Disagreements were solved by checking the articles, contacting authors and by consensus when needed.

RCTs and NRS were analyzed separately for each vaccine. Risk ratio (RR) was used for RCTs and cohort studies, and odds ratio (OR) for other study designs.

For vaccines with three or more studies published, results of individual studies were statistically combined to obtain a pooled estimate of the “average” effect on risk of relapse or MS. This procedure was only applied if studies did not show evidence of heterogeneity (i.e., significant variability between studies not due to chance). For the pooled estimate we used the DerSimonian and Laird random effects model with inverse variance weights, and for heterogeneity we used the Cochran’s Q statistic and the I2 statistic [7, 8]. I2 statistic measures the proportion of variability between studies, values of 40% or higher were considered significant and no pooled estimate was calculated.

Large studies are usually published regardless of effect size, but small studies have to be significant to be publishable, thus leading to a potential “publication bias”. We assessed this possibility by performing Begg and Egger tests. All analyses were performed using STATA v11.1 (Statacorp LP, TX, USA).

Results

Study selection

A total of 1,342 studies were identified through database searching of Medline, EMBASE and CENTRAL. Seven additional studies were identified through reference mining of review articles and relevant publications. Of these, 287 duplicates were removed and a total of 1,062 reports screened. After reviewing the abstracts, 932 studies were discarded because they did not clearly meet the inclusion criteria. Full text of the remaining 130 studies was assessed for eligibility, and 107 articles were excluded. Thus, 23 studies were included in the qualitative synthesis and 14 in the quantitative synthesis. The selection process is shown in the flow diagram in Fig. 1, and studies included are summarized in Supplementary Tables 1 and 2. The results of risk of bias assessment within and across studies are summarized for each individual study in the Supplementary Table 3.
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Fig. 1

Selection of studies for inclusion in the systematic review on the effect of immunizations on risk of developing multiple sclerosis and risk of MS relapse. A total of 23 reports were included in the qualitative synthesis and 14 in the final meta-analysis

We found at least one study in 18 of the original 23 vaccines examined. Enough information was gathered to obtain a pooled estimate for eight of these vaccines.

Study characteristics

BCG

Six studies were included in the analysis [914]. All were NRS, two nested case–control and the remaining four case–control studies. The outcome measured was the odds of developing MS. We did not find any evidence of a publication reporting risk of relapse in MS patients. The studies included involved 536 MS cases and 751 controls selected from the general population, the same hospitals or from the participating neurology department.

In all six studies, vaccination status was assessed retrospectively, with only one report [9] using health records to ascertain status. The rest used questionnaires, either self-administered, or performed by interviewers.

As summarized in Fig. 2a and Supplementary Table 1, all studies showed a consistent null effect of BCG on risk of developing MS (OR 0.96, 95% CI 0.69–1.34) with no evidence of heterogeneity as measured by the I2 statistic (0.0% and p value of 0.950). No evidence of publication bias, or bias of any other source was observed, and the average Newcastle–Ottawa (NOS) scale rating was 5.5 (see Supplementary Table 3). Overall, evidence found suggests BCG immunization may not be associated with increased risk of developing MS.
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Fig. 2

Study specific and pooled odds ratio/relative risks from studies on different immunization and MS. CI confidence interval

Chickenpox (Varicella)

We could find only one study linking risk of developing MS to chickenpox immunization, including 140 patients and 131 controls [14], in which authors reported a significantly high OR for chickenpox immunization and MS (OR 41.6, 95% CI 5.6–309.6). However, significance of these results was limited to a univariate analysis; no association was found in multivariate analysis, including socio-economic, environmental and family related variables. Thus, there is insufficient evidence on chickenpox immunization and the risk of developing MS or relapse.

Diphtheria

We found three studies reporting on the risk of developing MS after diphtheria immunization [12, 13, 15], and no study showing data regarding the risk of relapse. One study was a nested case–control and the remaining two were case–control reports. A total of 237 MS cases and 387 controls were included, and all used questionnaires to assess immunization.

As shown in Fig. 2b, pooled OR showed decreased risk of developing MS with diphtheria immunization, (0.60, 95% CI 0.40–0.90 and p value of 0.014). Even though we found no evidence of heterogeneity (I2 = 0.0% p = 0.627) and we thus calculated a pooled estimate, all the studies showed high risk of bias in the domain of blinding of participants, personnel and outcome assessors. This fact, together with the small number of patients included, should be taken into account when interpreting these results. Thus, there is some evidence that diphtheria immunization may be associated with a decreased risk of developing MS.

Diphtheria, pertussis, tetanus (DPT)

We could find only one study on the risk of developing MS with DPT immunization [10]. The study, which included 38 MS patients and 46 controls (relatives), reported an OR for DPT immunization and MS of 0.8 with a 95% CI 0.29–2.11. Thus, there is insufficient evidence to support any role of DPT immunization in MS.

Hepatitis A

We found one study on risk of developing MS after Hepatitis A immunization [16]. The study by DeStefano et al. [16] included 440 MS patients and 950 controls, and reported an OR for Hepatitis A vaccination and MS of 2.17 (with a 95% CI 0.5–9.5). We found no study showing data regarding the risk of relapse. Thus, there is insufficient evidence to support any role of Hepatitis A immunization on risk of developing MS.

Hepatitis B

We found eight NRS that addressed risk of developing MS [4, 1622], and one study reporting risk of relapse [23]. Of the former, four were nested case–control studies, two were case–control studies, one was a cohort study, and one was a before-and-after comparison. A total of 50,117 MS cases and 140,333 controls were included in the analysis of case–control studies.

Overall, the majority assessed immunization status consulting health records, avoiding potential recall bias. See Supplementary Table 3 for detailed results of risk of bias and quality assessment of each study.

As summarized in Supplementary Table 1 and Fig. 2c, a pooled estimate of the effect of the six case–control studies was calculated, obtaining a null OR of 1.00 (95% CI 0.74–1.37). Although p value was not significant (p = 0.099), evidence of moderate heterogeneity was found, with an I2 of 47.7%. We, therefore, explored potential sources of heterogeneity and found that the study by Geier and Geier [4] compared HBV immunization against tetanus immunization, while the others did not. When this study was excluded, heterogeneity was eliminated I2 of 0.00% (p = 0.870) and a more precise OR of 0.92 with 95% CI 0.84–1.004 was obtained. Regarding risk of relapse, the case-crossover study by Confavreux et al. [23] reported a relative relapse risk of 0.67 with a 95% CI 0.2–2.17.

Thus, there is suggestive evidence that Hepatitis B immunization is not associated with an increased risk of developing MS, and there is insufficient evidence in the case of risk of relapse.

Influenza

We found four studies describing OR of developing MS after influenza immunization [14, 16, 18, 20] and five studies showing risk of relapse [2327]. A total of 14,997 cases, and 10,128 controls were included in the meta-analysis on risk of developing MS; and 156 cases and 157 controls were analyzed for risk of relapse.

Pooled OR of developing MS and influenza immunization was 0.97 with a 95% CI of 0.77–1.23 and a p value of 0.873. We found little evidence of heterogeneity (I2 = 5.1% p = 0.368). There is, therefore, suggestive evidence against an increased risk of developing MS by influenza immunization (Fig. 2d)

Pooled relative risk (RR) of relapse following influenza immunization was 1.24 with a 95% CI of 0.89–1.72 and a p value of 0.2. We found no evidence of heterogeneity (I2 = 0.0% p = 0.531) (Fig. 2e). Hence, the evidence found suggests influenza immunization is not associated with increased risk of relapse.

We could not find any published evidence on effects of the new H1N1 vaccine and MS, probably due to its recent market release.

Measles

We found seven NRS addressing risk of MS [1316, 20, 28, 29], and we were unable to find studies reporting the risk of relapse. A total of 15,372 MS cases and 9,969 controls were included in the analysis of case–control studies.

When results of individual studies were pooled in a meta-analysis, we obtained an OR of 1.164 with a 95% CI of 0.754–1.798, but found evidence of significant heterogeneity (I2 = 70.6%, p = 0.002). We were only able to obtain a pooled estimate without significant heterogeneity (I2 = 4.1%, p = 0.390) when the study by Zorzon et al. was removed (OR 1.074, 95% CI of 0.974–1.185). Potential explanations for the discrepancy between Zorzon et al. and the other studies may lie in the fact that controls chosen were not sampled from the general population, but from blood donors, which may be different from MS patients or the general population. In addition, vaccination assessment was conducted by un-blinded face to face interview, thus potentially introducing recall bias (MS patients were more aware of their health, or interviewers asked more detailed questions, thus increasing chances of remembering being vaccinated). The evidence found suggests measles immunization is not associated with changes in risk of developing MS.

Measles, mumps, rubella (MMR)

We found three NRS that addressed the risk of MS [10, 16, 28], and we were unable to find studies reporting the risk of MS relapse. A total of 676 MS cases and 1,879 controls were included in the meta-analysis of case–control studies.

Pooled OR of developing MS and MMR immunization was 1.02 with a 95% CI of 0.64–1.61 and a p value of 0.704 (see Fig. 2f). We found no evidence of heterogeneity (I2 = 0.0%, p = 0.622). Hence, there is suggestive evidence that risk of MS is not altered by previous MMR immunization.

Mumps

We found five NRS addressing risk of developing MS [1315, 20, 28], and we were unable to find studies reporting risk of MS relapse. A total of 14,841 MS cases and 8,927 controls were included in the meta-analysis of case–control studies.

Pooled OR of developing MS and mumps immunization was 2.71 with a 95% CI of 0.81–9.09 but we found evidence of considerable heterogeneity (I2 = 73.8%, p = 0.004). We were able to obtain a pooled estimate without significant heterogeneity (I2 = 0.00%, p = 0.763) once again, when the study by Zorzon et al. was removed (OR 1.09, 95% CI 1.02–1.18). Therefore, the evidence suggests mumps immunization is not associated with changes in risk of developing MS.

Pertussis

We found two NRS that addressed risk of MS [13, 15], and we were unable to find studies reporting risk of MS relapse. The study by Kurtzke et al. [15] included 23 MS patients and 127 controls, and reported an OR for MS of 0.41 (95% CI 0.04–1.88). Work by Pekmezovic et al. [13] included 110 MS patients and 110 controls and reported also absence of MS risk (OR 1.0, 95% CI 0.6–1.8). Thus, there is insufficient evidence to support any role of Pertussis immunization in MS.

Pneumococcal

We were able to find only one report of the risk of developing MS and anti-pneumococcal immunization and no evidence regarding the risk of MS relapse [16]. The study by DeStefano et al. found no association (OR of 1.20 and 95% CI of 0.31–4.02), but, as suggested by the authors, too few cases or controls had been vaccinated in order to obtain an accurate estimate. Thus, there is insufficient evidence to support an association between anti-pneumococcal immunization and risk of MS.

Polio

We found seven NRS that reported risk of MS [1015, 29], and we were unable to find studies reporting risk of MS relapse. A total of 570 MS cases and 725 controls were included in the meta-analysis.

Pooled OR of developing MS and polio immunization showed a null association with an OR of 0.87 and a 95% CI of 0.61–1.25 (p = 0.462). We found evidence of some heterogeneity (I2 = 28.2%) but p value was not significant (p = 0.213) (see Fig. 2g). Thus, polio immunization may not be associated with an increased risk of developing MS.

Rabies

We found only two studies that addressed the risk of developing MS with rabies vaccination [10, 12] and both reports show a null association.

Thus, there is insufficient evidence to support a role of Rabies immunization in MS.

Rubella

We found five NRS that addressed risk of MS [12, 14, 16, 20, 28], and were unable to find studies reporting the risk of relapse. A total of 15,252 MS cases and 9,790 controls were included in the meta-analysis.

Pooled OR of developing MS and rubella immunization was 1.11 with a 95% CI of 0.65–1.90 and a p value of 0.704. We found evidence of high heterogeneity (I2 = 84.6%, p = 0.0001); this time, the study of Zorzon et al. could not explain heterogeneity as it persisted despite removal of the study from the analysis. Hence, there is conflicting evidence regarding rubella immunization and risk of developing MS.

Tetanus

We found eight NRS addressing risk of MS [12, 13, 15, 16, 18, 2931], and one study reporting the risk of MS relapse [23]. A total of 5,526 MS cases and 1,680 controls were included in the meta-analysis of case–control studies for risk of developing MS.

Pooled OR of developing MS and tetanus immunization was 0.68 with a 95% CI of 0.54–0.84 and a p value of 0.0001. We found little evidence of heterogeneity (I2 = 8.3%, p = 0.366) (Fig. 2h). Despite the lack of heterogeneity, and even though the number of cases and controls was higher than for diphtheria (the other immunization potentially showing decreased MS risk), caution should be used when interpreting these results. As shown in Supplementary Table 3, some of the studies included in the meta-analysis have NOS scores below 5, and high risk of bias in more than one domain. Therefore, evidence suggests that tetanus immunization may be associated with decreased risk of developing MS, but further research is needed to confirm this finding.

Typhoid fever

We found four NRS addressing risk of developing MS [12, 15, 29, 30], and were unable to find studies reporting the risk of MS relapse. A total of 393 MS cases and 529 controls were included in the meta-analysis of case–control studies.

We found no association between MS and typhoid fever immunization with an OR of 1.05 and a 95% CI of 0.72–1.53 and a p value of 0.704. We found little but not significant evidence of heterogeneity (I2 = 14.5%, p = 0.320) (Fig. 2i). Therefore, the evidence suggests there may not be any change in the risk of developing MS after typhoid fever immunization.

Yellow fever

We found two reports on yellow fever immunization and risk of developing MS [12, 15]. The study by Casetta et al. [12], including 104 MS patients, 150 controls with an OR of developing MS of 0.35 (95% CI 0.00–3.64), and the report by Kurtzke et al. [15], including 23 MS patients, 127 controls and an OR of 0.73 (95% CI 0.01–6.10). Thus, there is insufficient evidence to support any role of yellow fever immunization on risk of developing MS.

Discussion

All the evidence reported in this meta-analysis is summarized in Table 1, including quality of the evidence grading using the GRADE system [32].
Table 1

Summary of evidence

Vaccine

Risk of developing MS

Quality of evidence for risk of developing MS (GRADE)

Risk of a MS relapse

Quality of evidence for risk of MS relapse (GRADE)

References

BCG

Null

Moderate

No data

NA

[914]

OR (95% CI) 0.96 (0.69–1.34)

Chickenpox

Unclear

NA

No data

NA

[14]

Diphtheria

Decreased

Very low

No data

NA

[12, 13, 15]

OR (95% CI) 0.6 (0.4–0.9)

DPT

Unclear

NA

No data

NA

[10]

Hib

No data

NA

No data

NA

NA

Hepatitis A

Unclear

NA

No data

NA

[16]

Hepatitis B

Null

Moderate

Unclear

NA

[4, 1623]

OR (95% CI) 1.00 (0.74–1.37)

HPV

No data

NA

No data

NA

NA

Influenza

Null

Low

Null

Moderate

[14, 16, 18, 20, 2327]

OR (95% CI) 0.97 (0.77–1.23)

OR (95% CI) 1.24 (0.89–1.72)

Japanese encephalitis

No data

NA

No data

NA

NA

Measles

Unclear

NA

No data

NA

[1316, 20, 28, 29]

Meningococcal

No data

NA

No data

NA

NA

MMR

Null

Low

No data

NA

[10, 16, 28]

OR (95% CI) 0.93 (0.62–1.38)

Mumps

Unclear

NA

No data

NA

[1315, 20, 28]

Pertussis

Unclear

NA

No data

NA

[15]

Pneumococcal

Unclear

NA

No data

NA

[16]

Polio

Null

Moderate

No data

NA

[1015, 29]

OR (95% CI) 0.87 (0.61–1.25)

Rabies

Unclear

NA

No data

NA

[10]

Rotavirus

No data

NA

No data

NA

NA

Rubella

Unclear

NA

No data

NA

[12, 14, 16, 28]

Tetanus

Decreased

Low

Unclear

NA

[12, 13, 15, 16, 18, 23, 2931]

OR (95% CI) 0.68 (0.54–0.84)

Typhoid Fever

Null

Low

No data

NA

[12, 15, 23, 29, 30]

OR (95% CI) 1.05 (0.72–1.53)

Yellow Fever

Unclear

NA

No data

NA

[15, 23]

NA not applicable

MS is a demyelinating disorder, the precise etiology of which still remains largely unclear [33], yet it is commonly agreed that the onset of disease is influenced by genetic and environmental factors [34]. The importance of the environment has been recently highlighted by a study showing lack of genetic differences between monozygotic twins discordant for MS [35]. Evidence for involvement of the environment in MS development comes from a variety of epidemiological studies linking MS to latitude [36], vitamin D levels [37], smoking [38], and exposure to certain infections (mainly EBV) [39]. In the case of infections, many studies show the association of bacterial and viral infections with the onset of relapses [40, 41], while we have previously shown beneficial influence of chronic parasite infections on disease course [42]. It would, therefore, be valid to consider that immunization against a pathogen associated with higher risk of MS or relapse, would likely diminish the risk of disease. On the other hand, immunizations have been reported in some studies to be associated with increased risk of MS and relapse. These observations, together with case reports and some media coverage, may lead to doctors and patients to have doubts over immunizations given these conflicting results. This meta-analysis shows that none of the immunizations included in the quantitative analysis were associated with higher risk of developing MS or higher risk of relapse. In fact, diphtheria and tetanus immunization may be associated with a lower risk of MS, in agreement with a previously published report [43]. The mechanism through which these two vaccines may exert a protective effect remains unclear. In addition to the caveats mentioned before, we should add that for studies included in the diphtheria meta-analysis, it remains unclear whether any distinction was made between DPT and diphtheria alone; these results should therefore be taken with caution.

There is consensus that certain criteria should be met to determine causality, (i.e. tetanus immunization is the cause of the decreased risk of developing MS). In this case, since immunization preceded disease onset by many years and there is no evidence of latent infection or the lack of infections, per se, to meet causality criteria, as defined by Bradford Hill [44], is difficult.

We are fully aware of the limitations of a meta-analysis of mostly observational studies, and that interpretation of overall results should be considered with caution. In addition, combining data across studies to obtain pooled estimates is also subject to the drawback caused by the fact that MS patient ethnic characteristics, type of immunization and other variables may not be the same across the different studies. However, due to the nature of the intervention, and as a result of ethical and practical issues, most of the data found came from prospective or case–control studies, as will probably be the case for future data generated on the topic too, for that matter. With the generation of reporting guidelines for observational studies [45], more standardized studies could be performed in the future and more power obtained to ascertain potential associations between vaccines and MS.

In addition, some studies were separated by as much as 20 years, with the obvious changes in vaccine manufacturing technologies as well as serotypes. For example, in the case of influenza and risk of relapse, four studies were identified which included four different serotypes, three different manufacturers and 20 years elapsed between some of them [2427]. To address if the pooled estimates of the vaccines that were included in the meta-analysis have shifted over time, we performed a cumulative meta-analysis [46], where the evidence at the time a new study was published is calculated. We did not find any significant changes over time for any of the vaccines (data not shown). Unfortunately, we did not have sufficient data to stratify our analysis for other factors, and specific effects of strains and vaccine components remains elusive.

Evidence linking immunization to relapses is scarce. A study by Confavreux et al. [23] following a case-crossover design, reports no association for Hepatitis B or tetanus. Likewise, for influenza, there is also limited information. Even though we did not include case-reports or case-series in our study, we found a considerable number describing demyelinating events at variable time periods after several immunizations [4752]. These findings may be conflictive for both doctors and patients when deciding on immunization, especially in the case of vaccines that do not form part of mandatory national immunization programs or are recommended for travelers. Well-designed studies are necessary to address these concerns.

In conclusion, the review reveals no increase in risk of developing MS with BCG, hepatitis B, diphtheria, influenza, MMR, polio, tetanus and typhoid fever vaccines. We also report that diphtheria and tetanus immunization may be associated with a decreased risk of developing MS, and conclude further research is needed for varicella, DPT, haemophilus influenza b, hepatitis A, HPV, Japanese encephalitis, Measles, anti-meningococcal, mumps, pertussis, rabies, rotavirus, rubella, and yellow fever to ascertain potential association.

Acknowledgments

This study was supported by funding from the Raúl Carrea Institute for Neurological Research, FLENI.

Conflict of interest

None.

Supplementary material

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Supplementary material 1 (DOC 338 kb)
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Supplementary material 2 (PDF 476 kb)

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