On 11 June 2009, the WHO announced a pandemic caused by a novel H1N1 influenza A virus (2009 H1N1). When the 2009 H1N1 vaccine became available, many countries sought to vaccinate their general population. Because the 1976 H1N1 (swine) influenza vaccine caused a seven- to eightfold increase in the risk of Guillain–Barré syndrome (GBS; a form of acute paralysis) during the 42 days after vaccination (excess risk of approximately one GBS case per 100,000 vaccinees) in the USA Citation[1], there were concerns that a similar risk may be found with the 2009 H1N1 influenza vaccine. These concerns led to enhanced surveillance for GBS including active case identification in defined populations using standardized case definitions Citation[2]. Given the rarity of GBS overall (1–2 cases per 100,000 persons annually), studies of large populations were needed. In the USA, six large surveillance systems monitored more than 23 million vaccinated persons and data were combined through meta-analysis Citation[3]. In Europe, a case–control study was conducted of 50 million persons in Denmark, France, the Netherlands, Sweden and the UK Citation[4]. Other studies were also conducted in Canada Citation[5], Taiwan Citation[6] and Australia Citation[7]. An international collaboration brought together data from 10 countries Citation[8]. This was the most comprehensive examination of GBS following influenza vaccination ever conducted.
Despite the diverse populations studied, there was remarkable consistency in the results from these studies, with most demonstrating a two- to threefold increased risk of GBS in the 42 days following receipt of 2009 H1N1 vaccines. In the USA, all six surveillance systems reported a risk ratio greater than one with some individual results reaching statistical significance. The meta-analysis found a statistically significant increased risk of 2.4, which remained consistent across several sub-analyses. The international study found a relative incidence of 2.4 (95% CI: 1.6–3.7) in pooled data and 2.1 (95% CI: 1.3–3.4) using meta-analytic techniques. The international study also found highly consistent results in sensitivity analyses and a trend toward an increase in risk by age. An approximate twofold increase in the of risk GBS in the 42 days post-vaccination translates into approximately 1–3 excess cases of GBS per million people vaccinated.
Studies assessing the risk of GBS following influenza vaccination should carefully account for the potential risk of GBS from influenza illness; this was particularly important during the 2009 H1N1 pandemic since the vaccines became available in most countries at about the same time that the 2009 H1N1 wild-type virus was widely circulating. A recent study using combined data from the 2009 H1N1 and the 2010–2011 influenza seasons demonstrated that GBS was strongly associated with infection (odds ratio [OR]: 7.7; 95% CI: 4.5–26.9); by contrast, the same study found no significant increased risk (OR: 1.5; 95% CI: 0.6–4.0) for GBS following influenza vaccination Citation[9]. Also, influenza and other acute illnesses often decrease the likelihood of a person receiving vaccines (the ‘healthy vaccinee’ effect) and result in underestimation of the real risks associated with the vaccine, as the risk from vaccination may be higher among people with comorbidities. The many analyses completed during the 2009 H1N1 pandemic may not have been able to adequately adjust for either influenza-like illness or the healthy vaccine effect. Regardless, we believe the association between 2009 H1N1 vaccines and an increased risk of GBS is real since the US meta-analysis and the international study, both with sufficient power to detect a small increased risk of GBS, found that the risk of GBS post-vaccination remained unchanged after excluding cases with influenza-like symptoms. Furthermore, there was consistency across the many studies assessing this association during 2009 H1N1 influenza season as well as in earlier studies assessing the risk of GBS after seasonal influenza vaccines Citation[10,11].
Insights into how some illnesses increase the risk of GBS is shedding light on potential biological mechanisms by which influenza vaccines might cause GBS. There is strong evidence that molecular mimicry and autoimmune mechanisms underlie the pathophysiology of GBS Citation[12]. Gangliosides are important components of the peripheral nerves that vary by the number and position of their sialic acids. Different clinical forms of GBS are associated with different patterns of IgG autoantibodies to four gangliosides (GM1, GD1a, GT1a and GQ1b). For example, Campylobacter jejuni, which is associated with approximately 30% of all GBS cases worldwide Citation[12] has an outer membrane consisting largely of lipooligosaccharide and C. jejuni isolates from GBS patients bear GM1-like or GD1a-like lipooligosaccharide (and GQ1b for Miller Fisher syndrome, a variant form of GBS). Animal models indicate that this lipooligosaccharide can mimic gangliosides in inducing autoantibodies and result in GBS Citation[12]. Although the specific type of GBS primarily associated with C. jejuni is acute motor axonal neuropathy (AMAN), an autoimmune phenomenon is also probably responsible for acute inflammatory demyelinating polyneuropathy (AIDP), the most common type of GBS in the western hemisphere Citation[13].
Contamination by C. jejuni was considered a potential cause for the increased risk of GBS following receipt of the 1976 H1N1 influenza vaccines; however, Nachamkin et al. showed retrospectively that these vaccines were not contaminated by C. jejuni. They also showed that both the 1976 H1N1 and the seasonal 2004–2005 influenza vaccines induce GM1 antibodies (but not GBS) in mice Citation[14]. When influenza virus buds from host cells after replication, the virus may integrate extracellular sialic acid residues to form a complex that mimics host cell gangliosides. It has been hypothesized that administering this complex as a vaccine could activate the immune system and cause GBS Citation[14]. If this entire cascade occurs, it must occur rarely (roughly once per 100,000 vaccinees for the 1976 H1N1 influenza vaccine and per million vaccinees for the 2009 H1N1 influenza vaccines). Host genetic predisposition likely plays a role in predisposing to this rare complication.
Wang et al. found GM1 and GM2 antiganglioside polyclonal antibodies cross-react with multiple H1N1 and H3N2 influenza strains based on the degree of virus glycosylation Citation[15]. They also followed-up (in 2009) 46 persons previously vaccinated with 1976 H1N1 influenza vaccine and did not find anti-GM1, -GM2 or -GD1a antibodies in their serum. However, among 612 recipients of 2007–2008 or 2008–2009 influenza vaccines, 4 (all >60 years of age) had detectable antiganglioside antibody after immunization. They also injected mice with influenza vaccine and found the ability to induce antiganglioside antibodies varied by the strains of mice, suggesting a genetic role Citation[15]. One small study failed to detect antiganglioside antibodies in 6 mice, 8 GBS patients or 60 other humans who had received the 2009 H1N1 vaccine Citation[16]. Sejvar et al. have recently suggested some additional studies needed to better understand the biological mechanisms by which influenza vaccines may cause GBS including measuring the levels of antiganglioside antibodies in GBS patients Citation[17].
Despite our incomplete understanding of the biological mechanism, the consistent epidemiologic evidence demonstrating an increased risk of GBS following the 2009 H1N1 vaccines across different populations, in studies led by different investigators using different methods, provides strong evidence for a causal relationship. The 2009 H1N1 vaccine was the second time that GBS was found to be associated with an H1N1 vaccine, although the increase in risk is much lower for 2009 compared with 1976 H1N1 vaccines.
What is much less clear is whether there is a risk of GBS with annual influenza vaccines other than 1976 and 2009. The US Institute of Medicine (and Sejvar et al.) reviewed this topic in 2004 Citation[18] and 2012 Citation[19], and both times, concluded that the evidence was inadequate to accept or reject a causal relationship Citation[17]. This was not surprising as it is extremely difficult to ascertain an increase in risk of small magnitude (~two-fold increase) for an event as rare as GBS given a background rate of about 1 case of GBS per million persons during a 42-day risk window. The point estimate of the relative risk found with 2009 H1N1 vaccines is consistent with many of the earlier studies reviewed by IOM but, unlike most of the earlier studies, the 2009 H1N1 studies had adequate sample size and therefore statistical power for the primary GBS risk analysis as well as for exploring issues of confounding by influenza disease and seasonality. Even if annual influenza vaccines do increase the risk of GBS, the risk is unlikely to be in excess of 1–3 cases of GBS per million persons vaccinated. This small risk is much smaller than the risk of GBS following influenza illness Citation[9] and pales in comparison with the overwhelming benefits afforded by these vaccines given that influenza is responsible for an estimated 3000–49,000 deaths each season Citation[20].
Financial & competing interests disclosure
Halsey NA has served on safety monitoring boards for Novartis for studies of unrelated vaccines and he has provided expert testimony for GlaxoSmithKline for defense of a patent lawsuit for immunization schedules. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Disclaimer
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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