A total of 341,347 (29%) persons received >1 doses of an A(H1N1)pdm09 vaccine during the enrollment period. Of these, 278,131 (57%) received an A(H1N1)pdm09 vaccine only, 144,594 (30%) received a TIV only, and 63,216 (13%) received both. Almost all (96%) persons who received an A(H1N1)pdm09 vaccine received the adjuvanted Arepanrix either alone (78%) or in addition to a TIV (18%).

Although subcohorts might appear different when their aggregate characteristics are compared (Table 1), we based the actual analysis on the matched pairs (of vaccinated and unvaccinated matches) who were generally similar. As expected, children and younger adults dominated (54%) the A(H1N1)pdm09 vaccine group, whereas older (>55) adults (78%) and persons with chronic illnesses (30%) dominated the TIV group. There were more pregnant women in the vaccinated group, representing >50% of those who received the unadjuvanted A(H1N1)pdm09 vaccine. Vaccinated persons were more likely to have previously received the 2008–09 TIV and >1 pneumococcal vaccines.

By the end of the first year of follow-up, a total of 106 incident MS cases had been diagnosed among the unvaccinated cohort (Table 2), corresponding to an ASR of 24.2 (95% CI 20.1–28.3)/100,000 person-years, compared with 69 cases and an ASR of 20.2 (95% CI 15.4–24.9)/100,000 person-years among persons who received any influenza vaccine. The ASR was lower for persons who received Arepanrix (17.7 [95% CI 14.1–21.2]/100,000 person-years), corresponding to an ARR of 0.7 [95% CI 0.3–1.7]. The rate was similar for the unadjuvanted vaccine cohort. The ASR was higher for persons who received the 2009–10 TIV alone (36.8 [95% CI 25.0–48.6]/100,000 person-years) than for those who did not (ARR 1.5 [95% CI 0.3–6.8]). We observed no increase in risk for persons who received the TIV and A(H1N1)pdm09 vaccine concurrently. Regardless of vaccine type, ARRs calculated over the entire period (median of 3 years) were consistent with lack of association with vaccine administration.

After 1 year of follow-up, only 27 persons among the unvaccinated cohort met the case definition for having other demyelinating conditions, corresponding to an ASR of 6.9 (95% CI 2.6–11.1)/100,000 person-years, compared with 17 cases and an ASR of 4.7 (95% CI 0.0–10.6)/100,000 person-years among the vaccinated cohort (Table 3). Generally, ARRs calculated over this period were consistent with lack of an association with vaccine administration. Findings were similar over the longer follow-up period, except for persons who received an unadjuvanted vaccine where the ASR was higher (7.4 [95% CI 0.0–18.0]/100,000 person-years), but because of the small number of cases (<6), the corresponding ARR (2.1) was imprecise (95% CI 0.1–39.9).

In Cox models adjusted for matching (model A), we found no evidence of an association between MS and the receipt of any vaccine (Table 4). For instance, the hazard ratio for receipt of Arepanrix alone was 0.9 (95% CI 0.6–1.4) and did not appreciably change with further adjustment for receipt of the 2008–09 TIV (model B). We observed similar patterns when we measured disease occurrence over the entire follow-up period (Table 4).

In Cox models, we found no evidence of increased risk for other demyelinating conditions with the receipt of a pandemic vaccine (Table 4). The receipt of either TIV alone or concurrently with the adjuvanted pandemic vaccine was associated with an increased risk for these conditions and the association persisted after adjusting for receipt of the 2008–09 TIV and when repeated for the entire study period. However, although these findings were consistent, none of these associations was statistically significant or precise because few cases were diagnosed among these groups.

In this large population-based registry study, we found no evidence of an association between the adjuvanted influenza A(H1N1)pdm09 vaccine used in Canada and the incidence of MS or that of other acquired CNS demyelinating disorders. These findings are largely consistent with limited prior work regarding the A(H1N1)pdm09 vaccine and other influenza vaccines.

Few studies have examined the association between the A(H1N1)pdm09 vaccine and occurrence of MS. In published (mostly manufacturer-sponsored) randomized controlled trials conducted during the pandemic, there were no reports of clinically significant adverse events (including MS) of the different pandemic vaccine formulations (25). These findings are reassuring, but these trials might have not been large enough to detect a small increase in risk.

Similarly, vaccine adverse events surveillance systems in Europe and the United States did not detect increased risk for MS with pandemic vaccine use (26,27). No increased risk was found in an analysis of the European EudraVigilance database, which tracked reports of suspected autoimmune disorders after use of either adjuvanted (including Pandemrix) or unadjuvanted A(H1N1)pdm09 vaccines (26). Analyses of the US Vaccine Adverse Event Reporting System reached a similar conclusion (27).

A large retrospective record-linkage study from Sweden reported increased risk for paresthesias, but not of MS, among persons vaccinated with Pandemrix (8,28). Among persons with a high risk for influenza complications who were mostly vaccinated in the first 45 days of the campaign (healthcare workers, children, pregnant women, and persons with chronic diseases), the risk for MS was 1.17 (95% CI 0.82–1.66), and the risk estimates were highest within 6 weeks after vaccination (1.35 [95% CI 0.68–2.67]). There was no similar increase of risk among other groups. The authors attributed the excess risk among high-risk groups to possible confounding by underlying co-morbidity and vaccine indication.

Other AS03-adjuvanted influenza vaccines (e.g., avian influenza [H5N1] vaccines), as well as vaccines based on other oil-in-water adjuvants (e.g., MF59), were found in several randomized controlled trials to be more reactogenic than unadjuvanted TIVs. However, no serious adverse events, including MS, were reported (29). Finally, no evidence exists to support a link with use of unadjuvanted TIVs. In a systematic review, the authors identified 4 observational studies; the pooled risk ratio of developing MS after influenza vaccination was 0.97 (95% CI 0.77–1.23) with little evidence of heterogeneity (p = 0.368) (30).

We did not evaluate the association between A(H1N1)pdm09 vaccines and relapses in persons with established MS. The evidence for this association has been inconsistent. In several small randomized controlled trials, there was no increased incidence of relapses after A(H1N1)pdm09 vaccination (31,32). Observational studies provided conflicting findings, probably because of limitations in study design, such as small sample sizes and selection biases (33,34). Earlier studies and systematic reviews have not found any evidence of an increased risk for relapse with use of TIVs and other vaccines (35,36).

Evidence is scarce for an association between A(H1N1)pdm09 vaccination and other CNS demyelinating disorders. In a review of published case series, postmarketing surveillance data, and observational studies, a diagnosis of optic neuritis was not associated with influenza vaccination (37). Although 13 cases were reported after influenza vaccination, no association was found in 2 case–control studies (37). A more recent case–control study did not find an association between vaccine use in general and subsequent CNS demyelinating disorders (38).

We had access to accurate records of hospitalization, physician utilization, vaccination, and prescriptions for the entire population, which reduced the possibilities of selection bias and differential misclassification of exposures and outcomes and ensured that unvaccinated persons were truly enrolled and their healthcare use was captured. However, some variables might have been measured with error. The ascertainment of MS cases is most likely incomplete because initial symptoms might not be recognized as demyelinating, and diagnostic delays occur, although these have declined substantially over time in Manitoba (10) and elsewhere, such that most MS is diagnosed <1 year from onset (39). However, the incidence rate of MS for unvaccinated persons in this study was comparable with rates measured in similarly young populations in earlier studies from Manitoba and elsewhere (10,40). Furthermore, underascertainment is probably nondifferential with respect to A(H1N1)pdm09 vaccination because knowledge of vaccination status is unlikely to have directly influenced the way MS was diagnosed or coded, suggesting that our relative risk estimates of the association are likely to be accurate, even though our absolute MS incidence rates might be underestimated.

We did not have information about putative lifestyle and environmental risk factors. We attempted to adjust for these factors by matching on age, sex, region of residence, and PS. Matching on region reduces the likelihood of confounding by ethnicity because ethnic minorities tend to cluster in communities, even in the province’s large urban centers. PS reduces confounding by measured (e.g., access to healthcare) and unmeasured (e.g., smoking) confounders because of the inclusion of proxy conditions (e.g., smoking-related diseases) in the PS calculation. Furthermore, the vaccinated and unvaccinated cohorts were comparable, indicating a reasonable performance of the matching procedure. However, residual confounding remains possible.

Although the relatively large sample size permitted calculation of reasonably precise estimates, small numbers in some subgroup analyses limited the precision of estimates. Generalizability of the findings to other populations depends on their geographic location, ethnic composition, and access to the pandemic vaccine products. Manitoba’s population tends to be typical of many western populations, especially those in northern high-latitude countries, in terms of MS incidence and ethnic composition and even with the timing and epidemiology of the 2009 pandemic and the nature of the public health response to the pandemic. Finally, our findings might not be applicable to a future pandemic if the causative virus has a drastically different risk profile. However, we found no evidence that influenza virus antigenicity or pathogenicity influences the safety of commonly used adjuvant. Thus, our findings about the safety of the AS03 adjuvant are likely to hold true.

In conclusion, we found no evidence of increased short-term risk for MS or other acquired CNS demyelinating conditions after vaccination with an AS03-adjuvanted influenza A(H1N1)pdm09 vaccine. Therefore, it does not seem that the AS03 adjuvant, a candidate for inclusion in future pandemic vaccines, changes the safety profile of influenza vaccines with regard to MS. Although consistent with the lack of association with vaccination observed in the literature, our study findings do not rule out an increased (or decreased) risk for MS over the long term. Therefore, a similar analysis should be conducted once sufficient time has passed since the pandemic.

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