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 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.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-control13-15 and 12 self-controlled studies.16-27
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 cases 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 This results of this meta-analysis were confirmed after an updated systematic review in 2019.29 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.3,5-27,30 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.1 A self-controlled case series using French nationwide data from 2010 to 2014 found no association between seasonal influenza vaccination and GBS.31 A self-controlled risk interval by the FDA among Medicare beneficiaries found no increased risk of GBS following all 2015-2016 and 2016-2017 influenza vaccinations combined; however, an increased risk of GBS following high-dose vaccine specifically was found when limiting to either male beneficiaries (odds ratio: 3.33; 95% CI: 1.35-8.20) or beneficiaries at least 75 years of age (OR: 3.67; 95% CI: 1.52-8.85), suggesting a potential difference in risk between standard and high-dose vaccines.32 A self-controlled risk interval by the FDA among Medicare beneficiaries found no increased risk of GBS following standard dose, high dose, and all 2017-2018 influenza vaccinations combined; a slightly increased risk of GBS following the adjuvanted vaccine specifically was found (OR: 3.75; 95% CI: 1.01-13.96), though after multiplicity adjustment this finding was no longer statistically significant (p = 0.146).33 A self-controlled risk interval by the FDA among Medicare beneficiaries found no increased risk of GBS following high dose 2018-2019 influenza vaccinations.34 Additionally, two systematic reviews found that associations between influenza vaccination and GBS disappeared after adjusting for infection.35,36 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
A self-controlled analysis (within a case series cohort study using Medicare claims data) by the FDA found an increased risk of GBS in the 42 days following recombinant zoster vaccination (RZV) among Medicare beneficiaries 65 years and older (RR: 2.84; 95% CI: 1.53-5.27), corresponding to an attributable risk of 3 additional cases of GBS per million doses of Shingrix (95% CI, 0.62-5.64).37
Other than influenza and zoster vaccines, vaccines routinely used in the U.S. have not been shown to cause GBS. A 2016 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.38 A review of quadrivalent HPV vaccine safety data published between 2006 and 2015 found no increase in incidence of GBS compared to background rates.39 Most studies published since this 2006-2015 review have also found no increased risk of GBS following HPV vaccine,40-42 with the exception of one large cohort study in France published in 2017,43 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. A 2017 South Korean nationwide cohort study found no associations between HPV vaccination and 33 predefined serious adverse events (including GBS).44 A 2020 systematic review and meta-analysis found no association between HPV vaccines and many autoimmune or other rare diseases (including GBS).45 A 2020 meta-analysis found an increased risk of GBS following bivalent HPV vaccine (OR: 11.14; 95%CI: 2.00-61.92), but these results should be interpreted with caution given the very low number of GBS cases included in the analysis.46 A 2020 Chinese case-control study found no increased risk of GBS after any recommended pediatric or adult vaccination, including influenza.47 One rabies vaccine that contained sheep brain tissue was associated with GBS, but this vaccine is no longer used in the U.S.48
Analyses of safety surveillance data from the Vaccine Safety Datalink found no significant associations between mRNA COVID-19 vaccines and 23 serious health outcomes (including GBS).49 Self-controlled case series using national English and Scottish databases found an increased risk of GBS 15-21 days after vaccination with ChAdOx1nCoV-19, a viral vector COVID-19 vaccine not used in the US (IRR: 2.90; 95% CI: 2.15-3.92), but found no significant association with Comirnaty, the Pfizer-BioNTech COVID-19 vaccine.50
Preliminary safety surveillance data presented to ACIP on February 29th, 2024, suggested a potential increased risk for GBS after RSV vaccination among adults at least 60 years of age, but estimated that the benefits of RSV vaccination outweighed potential risks such as GBS.51Updated safety surveillance data presented to ACIP on June 26th, 2024, supported this interpretation, as the estimated numbers of avertable deaths, hospitalizations, and ICU admissions were much larger than potential GBS cases for both RSV vaccines among all age groups.52 Updated safety surveillance data presented to ACIP on October 24, 2024, supported this interpretation as well.53 Further studies are ongoing to confirm and more accurately quantify this suspected association.
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.52 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.55,56 The mechanism for other infectious agents associated with GBS has not been identified.1,16,57
* 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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