Initial links between Pandemrix and narcolepsy seemed limited to Nordic countries, Kelly Morris takes a look at growing evidence for a further reaching effect.

This February, the UK joined the list of countries reporting a spike of increased incidence of narcolepsy after vaccination against pandemic influenza A H1N1 2009 with Pandemrix. This study adds to the epidemiological data indicating a possible causal association, with a several-fold increased risk of the rare and debilitating sleep disorder after vaccination.

A possible link was first identified in Finland and Sweden in the summer of 2010; subsequently, cases of narcolepsy after vaccination were reported from France, Germany, Iceland, Ireland, Norway, the UK, and North America—many, but not all, were children or adolescents. Epidemiological studies first appeared in peer-reviewed journals in 2012, followed by more reports this year. However, before then, the prominent view, adopted by the European Medicines Agency, was that any association might be anomalous to Finland and Sweden.

Terhi Kilpi, director of the department of vaccination and immune protection at Finland’s National Institute for Health and Welfare (THL) told TLID that “the first thing we met was a huge silence from the scientific community, and we had a feeling that no one wanted to hear about this”. The recent reports are extremely important, she says, “because a growing number of experts and scientists are now willing to acknowledge that this actually happened. We now need to evaluate what this means in the field of vaccination, and to understand the mechanism behind this, rather than continue arguing whether or not it happened.” Kilpi recalls how most children in Finland were immunised in a massive 6 week effort in late 2009. In July, 2010, neurologist Markku Partinen from the Helsinki Sleep Clinic (Helsinki, Finland) called Kilpi to voice his concerns over a cluster of seven cases of childhood narcolepsy within 6 months of vaccination. Soon after, the Swedish Medical Products Agency reported a possible six cases of childhood narcolepsy after vaccination with Pandemrix. By August, known Finnish cases numbered 14, vaccination of the at-risk age group was halted in Finland, and studies were initiated.

In July, 2011, the European Vaccine Adverse Event and Surveillance Communication (VAESCO) network reported preliminary findings from a case-control study that pooled data from eight EU countries, and could not confirm an association between Pandemrix and narcolepsy outside of Finland and Sweden. On the basis of Finnish and Swedish data, the European Medicines Agency changed the indication for Pandemrix: “In persons under 20 years of age Pandemrix to be used only in the absence of seasonal trivalent influenza vaccines, following link to very rare cases of narcolepsy in young people.” The agency also concluded that overall the benefit-to-risk balance of Pandemrix remains positive, and Pandemrix continues to be licensed in the EU.

In Finland, calculations suggest that vaccination probably prevented 80 deaths as a cautious estimate, plus saving at least one pregnant woman and her unborn child. The current count of narcolepsy cases in Finland is around 100, while in Sweden the number may be double that, mainly in children but also younger adults. “The benefit compared to the harm now seems borderline in the vulnerable age group”, says Kilpi. “If I had known then what I know now, I would not have recommended the Pandemrix vaccine for children. But I did not.”

The manufacturer, GSK, has received almost 800 reports of narcolepsy that developed after Pandemrix immunisation, and, says company spokesman David Daley, “we have been working hard [since 2010] to better understand the research emerging from a select number of countries suggesting an association between Pandemrix and an increased risk of narcolepsy”. GSK is committed to further research into the potential role of the vaccine, he told TLID. “However”, he points out, “we currently believe that the available data are insufficient to assess the likelihood of a causal association. There is a need for further investigations, to disentangle the other factors—such as genetic, environmental, circulating infections—that we know are also associated with narcolepsy and may have played a role.”

What is known is that genetic risk, vaccine use, and means to detect cases varies between populations. Prevalence of the HLA type that confers susceptibility to narcolepsy is highest in northern Europeans, so lower population risk is likely to have weakened any signal in more diverse or ethnically different populations. Second, in countries such as the UK, where Pandemrix uptake was lower than in Finland, no link was found with passive surveillance but subsequently was with more rigorous study. THL is continuing immunological research to understand why some susceptible individuals reacted differently to the rest of the population.

Recent genetic research indicates that narcolepsy could be an autoimmune disorder resulting from defective antigen presentation by HLA to T cells. And, in China, research suggests that H1N1 infection could also precipitate narcolepsy, independent of vaccination. Emmanuel Mignot (Stanford University, CA, USA) told TLID that “there is little doubt seasonal infections and Pandemrix vaccination with H1N1 have contributed to triggering narcolepsy together with specific genetic factors”.

“Getting narcolepsy is probably a lot of accumulated bad luck, and in some cases Pandemrix has been one of the factors, with the adjuvant probably acting as an amplifier of the effect of the H1N1 vaccine”, Mignot concludes. One potential concern is the likelihood of detecting such an event when an immunisation campaign occurs over a longer period. “What if this had been a routine vaccine, how long would it have taken to detect it?” Kilpi asks. “So we need to invest strongly in our vaccine safety surveillance systems, and we need registry based follow-up to detect such events, we cannot rely on spontaneous reporting.” Finland and the UK are investigating any increase in other autoimmune disorders after Pandemrix, but data from Sweden are reassuring. Ongoing studies in Canada will attempt to elucidate why Arepanrix, which has the same adjuvant as Pandemrix, so far has not been found to carry the same risk of triggering narcolepsy.

In Finland, seasonal influenza vaccine uptake has gone down by about 10 percentage points in all age groups, and few children younger than 3 years have been vaccinated with free seasonal influenza vaccine. “Vaccines are traditionally well accepted here, but the failure to communicate explicitly that there is a tiny, tiny chance that something unexpected could happen, has left the parents of the children who fell ill feeling somehow betrayed”, notes Kilpi. “So we need to learn to communicate our recommendations more effectively and we will need to communicate explicitly that recommendations are based on best knowledge at that time but there is always the small chance that something unexpected occurs.”

Source: Lancet