Vaccines and Guillain-Barré Syndrome

The notion that Guillain-Barre syndrome (GBS) could be a consequence of vaccination was born of the swine influenza vaccine program administered in the United States in 1976. At the time, the estimated risk of GBS following receipt of the swine flu vaccine was estimated to be about 1 per 100,000 recipients. Since that time, the relationship between influenza vaccine and GBS has been variable. For example, Canadian researchers assessed the risk of GBS after seasonal influenza vaccination in Ontario, Canada, between 1993 and 2011. They found that the risk of GBS within six weeks of an influenza illness was much greater than after influenza vaccination. The attributable risks were one GBS admissions per million vaccinations compared with 17 GBS admissions per million influenza infections. Therefore, one could reasonably argue that influenza vaccine prevents GBS.

Additional studies listed below showed that neither measles, mumps, rubella, HPV, meningococcal conjugate, polio, pneumococcal, varicella, Hib, rabies, tetanus, diphtheria, hepatitis A, nor hepatitis B vaccines were associated with an increased risk of GBS.

References

Grimaldi-Bensouda L, Rossignol M, Kone-Paut I, et al.  Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: six years of case-referent surveillance. J Autoimmun 2017; 19:84-90.
The authors found that HPV vaccine did not increase the risk of autoimmune diseases (ADs) in females 11 to 25 years of age. ADs included central demyelination, multiple sclerosis, connective tissue disease, Guillain-Barre syndrome, type 1 diabetes, autoimmune thyroiditis, and idiopathic thrombocytopenic purpura. 

Andrews N, Stowe J, Miller E. No increased risk of Guillain-Barre syndrome after human papilloma virus vaccine: a self-controlled case-series study in England. Vaccine 2017;35:1729-1732.
The authors found no evidence of an increased risk of GBS following HPV vaccination in females ages 11 to 20 years in the United Kingdom, including no differences in risks following administration of either the bivalent or quadrivalent vaccines.

Gee J, Sukumaran L, Weintraub E, the Vaccine Safety Datalink Team. Risk of Guillain-Barre Syndrome following quadrivalent human papillomavirus vaccine in the Vaccine Safety Datalink. Vaccine 2017;35:5756-5758.
The Vaccine Safety Datalink (VSD) was utilized to conduct a rapid-cycle analysis to monitor the safety of the quadrivalent HPV vaccine (4vHPV) in real-time from August 2006 through October 2009. No cases of GBS were detected following administration of more than 600,000 doses among females 9 to 26 years of age. As GBS is rare, and the power to detect a risk is limited, VSD continued long-term surveillance from 2006 through 2015 in both males and females, following more than 2.7 million doses to determine the risk of GBS after receipt of 4vHPV. The rate of confirmed GBS within 42 days of vaccination was 0.36 cases per million vaccine doses, which was less than the published background rate in the general population of persons aged 11 to 18 years.

Martin Arias LH, Sanz R, Sainz M, Treceno C, Carvajal A. Guillain-Barre syndrome and influenza vaccines: a meta-analysis. Vaccine 2015;33:3773-3778.
The authors performed a meta-analysis of studies published between 1981 and 2014 to determine the risk of GBS following influenza vaccination. They found the receipt of any influenza vaccine (seasonal or pandemic) increased the risk of GBS by 1.4 (relative risk = 1.41). The RR of 1.41 is probably a reasonable average of the short-term (within 42 days) increased risk of GBS following influenza vaccination. An increased risk has been highly variable, detected in some seasons and not in others. In the seasons when an increased risk has been found, the relative risks have been around 2, which translates to an attributable risk of one additional case of GBS per million vaccinees. Of course, this just accounts for the risk side of the equation. Influenza infection is a stronger risk factor for GBS than is influenza vaccine; thus, during an entire influenza season, influenza vaccine actually decreases the risk of GBS by protecting against influenza infection.

Vellozzi C, Iqbal S, Stewart B, Tokars J, DeStefano F. Cumulative risk of Guillain-Barre syndrome among vaccinated and unvaccinated populations during the 2009 H1N1 influenza pandemic. Am J Public Health 2014;104:696-701.
The authors investigated the relative risk of GBS among 45 million people immunized with the influenza A (H1N1) 2009 monovalent vaccine. They found that by the end of the influenza season the vaccinated population had a lower cumulative risk of GBS compared with the unvaccinated population, indicating that vaccination by preventing influenza infection may have a potential protective effect on GBS.

Kwong JC, Vasa PP, Campitelli MA, Hawken S, Wilson K, et al. Risk of Guillain-Barre syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. Lancet Infect Dis 2013;13:769-776.
The authors assessed the risk of GBS after influenza infection or vaccination in Ontario, Canada, between 1993 and 2011. They found that the risk of GBS within six weeks of an influenza infection was greater than that following vaccination. The authors identified one GBS admission per million vaccinations compared with 17 GBS admissions per million cases of influenza infection.

Baxter R, Bakshi N, Fireman B, Lewis E, Ray P, et al. Lack of association of Guillain-Barre Syndrome with vaccinations. CID 2013;57(2):197-204.
The authors assessed the risk of GBS after vaccination with polio, MMR, conjugated pneumococcal, varicella, Haemophilus influenzae type b, rabies, influenza, any tetanus diphtheria combination, hepatitis A, or hepatitis B during a 13-year period and more than 30 million person-years. The authors did not find evidence of an increased risk of GBS following vaccination of any kind. Another important finding of this study was that recurrence of GBS following vaccination was extremely rare.

Greene SK, Rett MD, Vellozzi C, Li L, Kulldorff M, et al. Guillain-Barre Syndrome, influenza vaccination, and antecedent respiratory and gastrointestinal infections: a case-centered analysis in the Vaccine Safety Datalink, 2009-2011. PLoS ONE 2013;8(6):e67185.
The Vaccine Safety Datalink (VSD) team previously found GBS was significantly associated with monovalent inactivated (MIV) but not seasonal trivalent inactivated (TIV) influenza A (H1N1) vaccines during the 2009-10 influenza season, though results were possibly confounded by antecedent infections (see Greene SK, et al, 2012 above). In this follow-up study, the authors estimated the association between GBS and receipt of either 2009-20 MIV or 2010-11 TIV vaccines. They found that after adjusting for antecedent infections, there was no evidence for an elevated GBS risk following 1.27 million 2009-10 MIV or 2.8 million 2010-11 TIV doses.

Salmon DA, Proschan M, Forshee R, Garguillo P, Bleser W, et al.  Association between Guillain-Barre syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis. Lancet 2013;381:1461-1468.
The authors conducted a meta-analysis of data from six adverse-event-monitoring systems encompassing 23 million people vaccinated in the United States with monovalent influenza vaccine (MIV) to determine the risk of GBS. They found the 2009 H1N1 MIVs were associated with a small increased risk of GBS, which translated to about 1.6 excess cases of GBS per million people vaccinated. The authors also noted that the H1N1 disease peaked around the same time the H1N1 vaccine was administered, which likely confounded study findings.

Greene SK, Rett M, Weintraub ES, Li L, Yin R, et al. Risk of confirmed Guillain-Barre Syndrome following receipt of monovalent inactivated influenza A (H1N1) and seasonal influenza vaccines in the Vaccine Safety Datalink Project, 2009-2010. Am J Epidemiol 2012;175:1100-1109.
The Vaccine Safety Datalink (VSD) team determined the risk of GBS following receipt of monovalent inactivated (MIV) and seasonal trivalent inactivated (TIV) influenza A (H1N1) vaccines during the 2009-10 influenza season. The authors found GBS risk was significantly associated with MIV but not TIV within six weeks of vaccine receipt, though a causal association could not be proven as approximately half of the patients who received MIV also had an antecedent respiratory infection within one month of vaccination. Additionally, MIV became available at the same time as the peak of influenza activity during the 2009 H1N1 pandemic, while TIV preceded this peak.

Velentgas P, Amato AA, Bohn RL, Chan KA, Cochrane T, et al. Risk of Guillain-Barre syndrome after meningococcal conjugate vaccination. Pharmacoepidemiol Drug Saf 2012;21:1350-1358.
The authors identified no cases of GBS following receipt of more than 1.4 million doses of the meningococcal conjugate vaccine (MCV4) during a three-year period in the United States. The authors found that MCV4 vaccination was not associated with an increased risk of GBS.

Esteghamati A, Gouya MM, Keshtkar AA, Mahoney F. Relationship between occurrence of Guillain-Barre syndrome and mass campaign of measles and rubella immunization in Iranian 5-14 years old children. Vaccine 2008;26:5058-5061.
The authors investigated the occurrence of GBS after a four-week national immunization campaign in Iran in 2003 where 98 percent of the target population was vaccinated with measles vaccine, rubella vaccine, or both. Similar to other studies, the annual incidence of GBS remained relatively constant during the three-year period following vaccination, indicating that neither measles nor rubella vaccines were causally associated with GBS.

Patja A, Paunio M, Kinnunen E, Junttila O, Hovi T, et al.  Risk of Guillain-Barre syndrome after measles-mumps-rubella vaccination. J Pediatr 2001;138:250-254.
The authors found that the incidence of GBS following MMR vaccine was no higher than that previously reported in unvaccinated patients; they also found no clustering of cases of GBS at any time after vaccination. Additionally, MMR vaccination after recovery from GBS did not cause a relapse of the illness.

Reviewed by Paul A. Offit, MD on September 11, 2018

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