Conclusion
Influenza vaccines reduce the risk of influenza infection, which causes Guillain-Barré Syndrome (GBS). Thus, influenza vaccines prevent GBS by protecting against natural influenza infection. However, influenza vaccines can very rarely cause Guillain-Barré Syndrome (GBS) within 6 weeks of vaccination in adults, at an estimated rate of 1-3 cases per million vaccinations. Influenza vaccines have not been shown to cause GBS in children. Older formulations of rabies vaccine did cause GBS, but newer formulations of rabies vaccine have not been shown to cause GBS, and rabies vaccine is not routinely recommended to the general population in the United States. Other vaccines that are currently routinely recommended to the general population in the U.S.* have not been shown to cause GBS.
In most years when influenza vaccine strains are a good match for the circulating wild type viruses, influenza vaccines prevent much more GBS than the vaccines cause. [1, 2] Therefore, the very small risk of GBS from influenza vaccines pales in comparison to the benefits of the vaccine.
Why This is an Issue
In 1976, a new strain of influenza emerged that bore similarities to the strain that caused the deadly 1918 flu pandemic. A vaccine consisting of the inactivated strain was prepared and administered to mitigate the impact of a pandemic if it were to occur. Fortunately, the feared pandemic never occurred. However, safety surveillance installed and expanded as part of this program picked up clusters of GBS in the recently vaccinated. Although this adverse event was quite rare, it was shown to be significantly associated with this particular vaccine, and the program was terminated in late 1976 amid much public criticism. Enhanced surveillance for GBS after influenza vaccination has been conducted since this time [1, 3].
Epidemiological Evidence
The incidence of GBS due to all causes has been estimated as 0.4-4.0 cases per 100,000 person-years, with higher rates with increasing age [1]. Clinical trials do not approach the size necessary to examine a potential causal association between vaccines and a rare adverse event like GBS [4]. A systematic literature review identified 24 relevant controlled studies with unduplicated data, including 9 cohort [3, 5-12], 3 case-control [13-15] and 12 self-controlled studies [16-27]. The association with influenza vaccines discussed below was age related showing decreasing risk with decreasing age. The available evidence did not reveal an increased risk in children.
Adults who received the 1976-77 swine flu vaccine were 9.5 (95% Confidence Interval: 8.2-10.3) times more likely to develop GBS compared to those who did not receive the vaccine [3]. This increased risk was primarily in the six weeks following vaccination, translating into about one excess case per 100,000 vaccinations. Without the widespread pandemic of swine influenza anticipated in 1976, this risk of GBS led to the cessation of the 1976-77 flu vaccine campaign.
Since the 1976-77 influenza season, safety surveillance has monitored GBS after influenza vaccination closely. The level of risk seen in 1976-77 has been ruled out in these studies. A meta-analysis of 6 active surveillance systems in the U.S. in the 2009-10 influenza season showed a small statistically significant increased risk of GBS in the 42 days after pandemic H1N1 influenza vaccination (incident rate ratio 2.35; 95% CI 1.53-3.68) [22]. An international collaboration in the 2009-10 influenza season combining data from Australia, Canada, China, Denmark, Finland, the Netherlands, Singapore, Spain, the UK, and the U.S. found a similarly small but significant increase in risk during the 42 days post pandemic H1N1 vaccination (relative incidence 2.42; 95% CI 1.58-3.72) [21]. A 2015 meta-analysis also found a small but significant increase in risk of GBS following influenza vaccination (relative risk 1.41; 95% CI 1.20-1.66), although the risk was higher for pandemic vaccines (RR 1.84; 95% CI 1.36-2.50) than for seasonal vaccines (RR 1.22; 95% CI 1.01-1.48) [28]. These three meta-analyses indicate an approximate doubling of risk of GBS in the six weeks following pandemic H1N1 influenza vaccination. This is also consistent with estimates of risk of GBS in many studies of seasonal influenza vaccine, many of which were underpowered to show such a small increase in risk with statistical significance [3, 5-27, 29]. This doubling of risk translates into only 1-3 excess cases of GBS per million persons vaccinated, with a higher attributable risk among older populations due to a higher background rate of GBS among older populations. The evidence for post-influenza vaccine GBS among children is inadequate to draw definitive conclusions. The risk for GBS post-influenza vaccine is much less than the estimated risk after wild-type influenza infection, providing further evidence that the benefits of influenza vaccination greatly outweigh the risks [1].
Other than influenza vaccines, vaccines routinely used in the U.S. have not been shown to cause GBS. A retrospective observational study of California infants found no cases of GBS during the 30-day risk interval after 46,486 doses of DTaP-IPV/Hib vaccine administered [30]. A review of quadrivalent HPV vaccine safety data published between 2006 and 2015 found no increase in incidence of GBS compared to background rates [31]. Most studies published since this 2006-2015 review have also found no increased risk of GBS following HPV vaccine [32-34], with the exception of one large cohort study in France [35], which found a positive association between HPV vaccine and GBS (adjusted hazard ratio 3.78; 95% CI 1.79-7.98), resulting in an attributable risk of 1-2 GBS cases per 100,000 girls vaccinated against HPV. One rabies vaccine that contained sheep brain tissue was associated with GBS, but this vaccine is no longer used in the U.S. [36]. A self-controlled analysis by the FDA found an association between recombinant zoster vaccination (RZV), also known as Shingrix, and Guillain Barré Syndrome (GBS) [37]. The rate ratio, comparing cases in risk versus control windows, was 2.34 (95% Confidence Interval: 1.01-4.31); this corresponds to an attributable risk of 73 additional cases of GBS per million doses of Shingrix (95%CI: 0.62-5.64). However, these results should be interpreted with caution, as the number of cases in the study was small (24 in risk window versus 20 in control window). In addition, a large, prospective VSD study in adults 50 years of age and older did not find an association using well-visit comparators (relative risk 0.92, 95% CI 0.34-2.52) [38]. In addition, there is a risk of GBS after an episode of herpes zoster, with a rate ratio of 6.3 (95% CI 1.8-21.9) for those under 65 and 4.1 (95% CI 1.9-8.7) for those 65 and older, which the vaccine should prevent [39].
Proposed Biological Mechanism
Most GBS cases are preceded by a recent respiratory or gastrointestinal infection. Campylobacter jejuni, which causes gastrointestinal infections, is the most common specific infectious agent identified through molecular mimicry [40]. Campylobacter jejuni induces antibodies that react against GM1 gangliosides in human neurons due to shared antigenic and epitopic features with lipo-oligosaccharide moieties on the cell wall of the Campylobacter bacterium [41, 42]. The mechanism for other infectious agents associated with GBS has not been identified [1, 16, 43].
* These conclusions do not necessarily consider vaccines recommended only for special populations in the United States such as Yellow Fever vaccine (international travelers) or Smallpox vaccine (military personnel), or vaccines not currently recommended to the public, such as the Janssen COVID-19 vaccine.
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