Among the more than one million people vaccinated with the squalene adjuvanted Pandemrix vaccine in Stockholm county (the only vaccine used in Sweden against pandemic H1N1), the risks of Bell’s palsy and paraesthesia were increased. Excess risks for Bell’s palsy, paraesthesia, and inflammatory bowel disease were, however, observed only among those vaccinated in the early phase of the vaccination campaign (≤45 days), when high risk groups predominated. In contrast, among people vaccinated after the first 45 days of the campaign, representing more closely the general population, we found no statistically significant associations between vaccination and autoimmune or neurological diseases. Change in the risks for Guillain-Barré syndrome, multiple sclerosis, diabetes, or rheumatoid arthritis was not evident in any of the analyses. As to the risk of narcolepsy in adolescents and children, small numbers precluded any meaningful conclusions.
People vaccinated in the first 45 days consistently more often had a previous diagnosis of neurological or autoimmune disease than those who remained unvaccinated. Earlier neurological and autoimmune disease was therefore a strong predictor for vaccination in the first 45 days—for example, those with type 1 diabetes were at a sixfold increased risk of being vaccinated early. Together with the high proportion reported to have a high risk condition according to the Vaccinera database, this suggests that the national recommendation to vaccinate high risk groups first was followed. Earlier comorbidity could explain some of the excess risks seen in those vaccinated early. Even if hazard ratios decreased for almost all outcomes (for example, Bell’s palsy from 1.49 to 1.34; inflammatory bowel disease from 1.43 to 1.25, and paraesthesia from 1.43 to 1.25) after adjustment for the number of hospital admissions and visits to specialist care, some residual confounding may still exist. These small excess risks may be partly or entirely explained by other factors that were not captured by a crude measure of healthcare utilisation. Nevertheless, if true, these hazard ratios would translate into low absolute risks.
In contrast, those vaccinated in the later part of the campaign had a similar distribution of earlier neurological and autoimmune disease (with the exception of a small increase in previous inflammatory bowel disease) as unvaccinated people. Furthermore, those in this subcohort were at no statistically increased risk of any of our analysed outcomes, suggesting that in a general population vaccination with Pandemrix is unlikely to lead to an important effect on the risk for neurological or autoimmune diseases (not accounting for risk of narcolepsy). However, mortality, even after adjustment for previous healthcare utilisation in addition to age, sex, and socioeconomic status, was lower in this vaccinated subcohort than in the unvaccinated cohort. This may reflect a healthy selection of people for those vaccinated and that our risk estimates for neurological and autoimmune outcomes may be underestimates.
Comparisons with previous studies and findings
Most available data on the safety of A (H1N1) pandemic vaccines—with Pandemrix being the most commonly used vaccine in the European Union (estimated use in some 30 million)—are based on reports of spontaneous adverse drug events to national regulatory agencies. Such data have been generally reassuring during and after the pandemic period. However, an increased risk of narcolepsy in children and adolescents, with increased relative risks ranging from fourfold to ninefold, have been recently reported from authorities in Sweden and Finland,17 18 19
leading to regulatory action by the European drug regulatory body, the European Medicines Agency, in July 2011 to restrict the use of Pandemrix vaccinations.25
Regarding other outcomes, some pertinent conclusions can be drawn from published studies on the safety of influenza vaccinations in general.
Although previous studies have produced conflicting results on an association between Guillain-Barré syndrome and influenza vaccination,8 9 10 26
two larger studies reported no positive association.27 28
In our study we found no association between vaccination with an adjuvanted H1N1 vaccine and Guillain-Barré syndrome. Our findings are consistent with a Chinese study of a non-adjuvanted pandemic vaccine14
and add to that study because we were able to estimate hazard ratios and our study population was not restricted to previously healthy people.
Although a large number of studies have examined the association between various types of vaccinations and type 1 diabetes,29 30 31 32
none has shown an association.33
To our knowledge no studies have been carried out on influenza vaccinations (for example, using squalene adjuvanted vaccines) and risk of type 1 diabetes. In our study we found no association between H1N1 vaccination and type 1 diabetes in the age group where most cases of the disease occur (those born in 1990 and later).
The excess risk for paraesthesia may constitute a local symptom (for example, pain, redness, swelling, tingling) at the injection site from the H1N1 vaccination. The excess risk of paraesthesia was only of borderline significance (95% confidence interval 1.00 to 1.23) and absent in patients undergoing vaccination in the late phase.
We cannot explain the small increase in risk for Bell’s palsy seen in this study. Potential causes include viral infection and pregnancy, neither of which could be dealt with using the data in our analyses. The absolute risk of Bell’s palsy was low, 6.4 cases per 100
000 vaccinated population.
Safety considerations of European Medicines Agency for adjuvanted pandemic A (H1N1) vaccines
The pandemic vaccines were developed by using a prototype vaccine that contained the H5N1 antigen and an adjuvant—for Pandemrix, squalene combined with DL-α-tocopherol. This mock-up vaccine was recommended for approval in 2008 by the European Medicines Agency, based on data on efficacy (antibody response) and safety in some 5000 people aged 18-65 years. After approval of the final vaccine in September 2009, a trial was carried out in 300 children aged 3-12 years. Thus at the time of release on to the market in October 2009 the safety experience of Pandemrix was deemed to be limited. The European Medicines Agency encouraged a strategy for enhanced pharmacovigilance, implying stimulated reporting of spontaneous adverse drug reactions and the start of epidemiological studies. During and after the pandemic vaccination period in Sweden, reports on adverse drug reactions for Pandemrix were generally reassuring but produced a new signal for allergic reactions. In the autumn of 2010 an unexpectedly large number of reports on narcolepsy in adolescents and children was noted by the Medical Products Agency in Sweden (as in Finland).18
Subsequent epidemiological studies in Sweden and Finland reported several-fold increased risks of narcolepsy in children and adolescents.17 18 19
Our trial is the first data based study on an array of neurological and autoimmune safety outcomes for one of the pandemic vaccines used in the European Union.
Strengths and limitations of the study
Through the vaccination register (Vaccinera) our study covered all vaccinated people in Stockholm county. The unique personal identity number enabled us to ascertain data on earlier utilisation of healthcare as well as to adjust for sex, age, and socioeconomic status. We used ICD codes assigned by doctors to identify neurological and autoimmune diseases recorded in the Stockholm healthcare database. Our large number of study participants allowed for precise risk estimates for many of the outcomes. For instance, for a rare disease such as Guillain-Barré syndrome we could rule out a hazard ratio of 1.7 or greater (table 3). Through data on healthcare utilisation before the pandemic period we could also explain at least part of the excess risks seen in those vaccinated early against H1N1.
Our study has some limitations that may have influenced our risk estimates. The neurological and autoimmune diseases studied were diagnosed and entered in the healthcare database as part of the clinical routine in the county and thus depended on patients seeking healthcare because of their greater availability for specialist care. We also lacked detailed data on covariates, with the possibility for residual confounding. For instance, the lower mortality in those vaccinated in the late phase was not explained through adjustment for earlier healthcare utilisation. If people in this subcohort are healthier than the general population our study may have underestimated the risk of adverse effects in those who were vaccinated. Two circumstances argue against our hazard ratios being underestimates. Firstly, neurological and autoimmune diseases were similar in people of this subcohort undergoing late vaccination and in the unvaccinated cohort. Secondly, as cardiovascular disease and cancer are by far the most common causes of death in Sweden, the lower mortality in those vaccinated should be sought in low levels of smoking or a low body mass index. However, neither smoking nor high body mass index is a major risk factor for neurological or autoimmune diseases, and therefore a skewed distribution of these characteristics is unlikely to hide a true association between H1N1 vaccination and our outcomes.
Furthermore, high risk groups were over-represented in the early phase of the vaccination campaign (as shown by a higher prevalence at the start of follow-up for most of the selected outcome diagnoses). This implies that this subgroup is not obviously comparable with the unvaccinated subgroup, thus potentially leading to selection bias. Since we have access only to data on visits to specialist care and hospital admissions, surveillance bias is also a concern—namely, that vaccinated patients may have better access to specialist care than unvaccinated patients, especially those belonging to medical risk groups. To some extent we controlled for both selection bias and surveillance bias by adjustment for healthcare utilisation before the start of follow-up, which generally resulted in reduced risk estimates. Residual confounding is, however, still a possibility.
Overall, 90% of the vaccinated people had a follow-up time ranging from 256 days to 315 days. For certain conditions requiring a long period of investigation or if an adverse effect of the vaccination is delayed, the follow-up time may be too short to reveal the full effect, which would result in an underestimation of the true effect. The influence of chance is a problem when evaluating multiple end points divided according to two temporal aspects. Furthermore, the power of our study to detect change of risk for rare outcomes such as narcolepsy was insufficient.
Conclusions and implications
Based on data from follow-up during 8-10 months among more than one million people vaccinated with Pandemrix and 900
000 unvaccinated people in the entire population of Stockholm county, we found mostly reassuring results, notably for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. Although we found small excess risks (ranging from 1.25 to 1.34) for some neurological and autoimmune diseases after vaccination, such as Bell’s palsy, paraesthesia, and inflammatory bowel disease, these were only seen in those among high risk groups targeted for early vaccination and who were likely to have earlier comorbidity, which could partly or entirely have explained the findings. As to the association between vaccination with Pandemrix and narcolepsy in adolescents and children, small numbers precluded meaningful results.
What is already known on this topic
- Studies are lacking on adverse events (except for narcolepsy) with any of the three vaccines used in the European Union against H1N1 during the pandemic period
- Available data are limited to case series or highly selected populations with short follow-up or no control group
What this study adds
- Excess risks for Bell’s palsy, paraesthesia, and inflammatory bowel disease after H1N1 vaccination with adjuvanted Pandemrix in Sweden were small but significant among more than one million vaccinated, but only in high risk groups targeted for early vaccination and who were likely to have earlier comorbidity
- The risk of Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged
- Small numbers of children and adolescents with narcolepsy precluded any meaningful conclusions