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-control 13-15 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 51. Updated 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. 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 51. 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 52,53. The mechanism for other infectious agents associated with GBS has not been identified 1,16,54.
* 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.
References
1. Vellozzi C, Iqbal S and Broder K. Guillain-Barre syndrome, influenza, and influenza vaccination: the epidemiologic evidence. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2014; 58: 1149-1155. 2014/01/15. DOI: 10.1093/cid/ciu005.
2. Halsey NA, Talaat KR, Greenbaum A, et al. The safety of influenza vaccines in children: An Institute for Vaccine Safety white paper. Vaccine 2015; 33 Suppl 5: F1-f67. 2016/01/30. DOI: 10.1016/j.vaccine.2015.10.080.
3. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976–1977. American journal of epidemiology 1979; 110: 105-123. 1979/08/01. DOI: 10.1093/oxfordjournals.aje.a112795.
4. Ellenberg SS and Braun MM. Monitoring the safety of vaccines: assessing the risks. Drug Saf 2002; 25: 145-152. 2002/04/12.
5. Johnson DE. Guillain-Barre syndrome in the US Army. Archives of neurology 1982; 39: 21-24. 1982/01/01.
6. Hurwitz ES, Schonberger LB, Nelson DB, et al. Guillain-Barre syndrome and the 1978-1979 influenza vaccine. New England Journal of Medicine 1981; 304: 1557-1561.
7. Kaplan JE, Katona P, Hurwitz ES, et al. Guillain-Barre syndrome in the United States, 1979-1980 and 1980-1981. Journal of the American Medical Association 1982; 248: 698-700.
8. Roscelli JD, Bass JW and Pang L. Guillain-Barre syndrome and influenza vaccination in the US Army, 1980-1988. American journal of epidemiology 1991; 133: 952-955.
9. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barre syndrome and the 1992-1993 and 1993-1994 influenza vaccines. New England Journal of Medicine 1998; 339: 1797-1802.
10. Greene SK, Kulldorff M, Lewis EM, et al. Near real-time surveillance for influenza vaccine safety: Proof-of-concept in the vaccine safety datalink project. American journal of epidemiology 2010; 171: 177-188.
11. Ho TY, Huang KY, Huang TT, et al. The Impact of Influenza Vaccinations on the Adverse Effects and Hospitalization Rate in the Elderly: A National Based Study in an Asian Country. PloS one 2012; 7.
12. Kawai AT, Li L, Kulldorff M, et al. Absence of associations between influenza vaccines and increased risks of seizures, Guillain-Barre syndrome, encephalitis, or anaphylaxis in the 2012-2013 season. Pharmacoepidemiology and drug safety 2014; 23: 548-553.
13. Grimaldi-Bensouda L, Alperovitch A, Besson G, et al. Guillain-barre syndrome, influenzalike illnesses, and influenza vaccination during seasons with and without circulating A/H1N1 viruses. American journal of epidemiology 2011; 174: 326-335.
14. Galeotti F, Massari M, D’Alessandro R, et al. Risk of Guillain-Barre syndrome after 2010-2011 influenza vaccination. European Journal of Epidemiology 2013; 28: 433-444.
15. Dieleman J, Romio S, Johansen K, et al. Guillain-Barre syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: Multinational case-control study in Europe. BMJ (Clinical research ed) 2011; 343.
16. Stowe J, Andrews N, Wise L, et al. Investigation of the temporal association of Guillain-Barre syndrome with influenza vaccine and influenzalike illness using the United Kingdom general practice research database. American journal of epidemiology 2009; 169: 382-388.
17. Juurlink DN, Stukel TA, Kwong J, et al. Guillain-Barre syndrome after influenza vaccination in adults: A population-based study. Archives of Internal Medicine 2006; 166: 2217-2221.
18. Hughes RA, Charlton J, Latinovic R, et al. No association between immunization and Guillain-Barre syndrome in the United Kingdom, 1992 to 2000. Archives of Internal Medicine 2006; 166: 1301-1304.
19. Baxter R, Bakshi N, Fireman B, et al. Lack of association of Guillain-Barre syndrome with vaccinations. Clinical Infectious Diseases 2013; 57: 197-204.
20. Burwen DR, Ball R, Bryan WW, et al. Evaluation of Guillain-Barre syndrome among recipients of influenza vaccine in 2000 and 2001. American journal of preventive medicine 2010; 39: 296-304.
21. Dodd CN, Romio SA, Black S, et al. International collaboration to assess the risk of Guillain Barre Syndrome following Influenza A (H1N1) 2009 monovalent vaccines. Vaccine 2013; 31: 4448-4458.
22. Salmon DA, Proschan M, Forshee R, 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. 2013/03/19. DOI: 10.1016/s0140-6736(12)62189-8.
23. Huang WT, Yang HW, Liao TL, et al. Safety of Pandemic (H1N1) 2009 Monovalent Vaccines in Taiwan: A Self-Controlled Case Series Study. PloS one 2013; 8.
24. Prestel J, Volkers P, Mentzer D, et al. Risk of Guillain-Barre syndrome following pandemic influenza A(H1N1) 2009 vaccination in Germany. Pharmacoepidemiology and drug safety 2014 2014/05/13. DOI: 10.1002/pds.3638.
25. Greene SK, Rett MD, Vellozzi C, 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.
26. Kwong JC, Vasa PP, Campitelli MA, et al. Risk of Guillain-Barre syndrome after seasonal influenza vaccination and influenza health-care encounters: A self-controlled study. The Lancet Infectious Diseases 2013; 13: 769-776.
27. McCarthy NL, Gee J, Lin ND, et al. Evaluating the safety of influenza vaccine using a claims-based health system. Vaccine 2013; 31: 5975-5982. 2013/10/24. DOI: 10.1016/j.vaccine.2013.10.031.
28. Martin Arias LH, Sanz R, Sainz M, et al. Guillain-Barre syndrome and influenza vaccines: A meta-analysis. Vaccine 2015; 33: 3773-3778. 2015/05/23. DOI: 10.1016/j.vaccine.2015.05.013.
29. Sanz Fadrique R, Martín Arias L, Molina-Guarneros JA, et al. Guillain-Barré syndrome and influenza vaccines: current evidence. Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia 2019; 32: 288-295. 2019/06/25.
30. Sandhu SK, Hua W, MaCurdy TE, et al. Near real-time surveillance for Guillain-Barre syndrome after influenza vaccination among the Medicare population, 2010/11 to 2013/14. Vaccine 2017; 35: 2986-2992. 2017/04/30. DOI: 10.1016/j.vaccine.2017.03.087.
31. Grave C, Boucheron P, Rudant J, et al. Seasonal influenza vaccine and Guillain-Barré syndrome: A self-controlled case series study. Neurology 2020; 94: e2168-e2179. 2020/02/27. DOI: 10.1212/wnl.0000000000009180.
32. Arya DP, Said MA, Izurieta HS, et al. Surveillance for Guillain-Barré syndrome after 2015-2016 and 2016-2017 influenza vaccination of Medicare beneficiaries. Vaccine 2019; 37: 6543-6549. 2019/09/14. DOI: 10.1016/j.vaccine.2019.08.045.
33. Perez-Vilar S, Wernecke M, Arya D, et al. Surveillance for Guillain-Barre syndrome after influenza vaccination among U.S. Medicare beneficiaries during the 2017-2018 season. Vaccine 2019; 37: 3856-3865. 2019/05/28. DOI: 10.1016/j.vaccine.2019.05.041.
34. Perez-Vilar S, Hu M, Weintraub E, et al. Guillain-Barré Syndrome After High-Dose Influenza Vaccine Administration in the United States, 2018-2019 Season. The Journal of infectious diseases 2021; 223: 416-425. 2020/11/03. DOI: 10.1093/infdis/jiaa543.
35. Demicheli V, Jefferson T, Di Pietrantonj C, et al. Vaccines for preventing influenza in the elderly. The Cochrane database of systematic reviews 2018; 2: Cd004876. 2018/02/02. DOI: 10.1002/14651858.CD004876.pub4.
36. Wachira VK, Peixoto HM and de Oliveira MRF. Systematic review of factors associated with the development of Guillain-Barré syndrome 2007-2017: what has changed? Tropical medicine & international health : TM & IH 2019; 24: 132-142. 2018/11/18. DOI: 10.1111/tmi.13181.
37. Goud R, Lufkin B, Duffy J, et al. Risk of Guillain-Barré Syndrome Following Recombinant Zoster Vaccine in Medicare Beneficiaries. JAMA Internal Medicine 2021; 181: 1623-1630. DOI: 10.1001/jamainternmed.2021.6227.
38. Hansen J, Timbol J, Lewis N, et al. Safety of DTaP-IPV/Hib vaccine administered routinely to infants and toddlers. Vaccine 2016; 34: 4172-4179. 2016/07/05. DOI: 10.1016/j.vaccine.2016.06.062.
39. Vichnin M, Bonanni P, Klein NP, et al. An Overview of Quadrivalent Human Papillomavirus Vaccine Safety: 2006 to 2015. The Pediatric infectious disease journal 2015; 34: 983-991. 2015/06/25. DOI: 10.1097/inf.0000000000000793.
40. Andrews N, Stowe J and 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. 2017/03/02. DOI: 10.1016/j.vaccine.2017.01.076.
41. Gee J, Sukumaran L and Weintraub E. Risk of Guillain-Barre Syndrome following quadrivalent human papillomavirus vaccine in the Vaccine Safety Datalink. Vaccine 2017; 35: 5756-5758. 2017/09/25. DOI: 10.1016/j.vaccine.2017.09.009.
42. 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. Journal of autoimmunity 2017; 79: 84-90. 2017/02/14. DOI: 10.1016/j.jaut.2017.01.005.
43. Miranda S, Chaignot C, Collin C, et al. Human papillomavirus vaccination and risk of autoimmune diseases: A large cohort study of over 2million young girls in France. Vaccine 2017; 35: 4761-4768. 2017/07/29. DOI: 10.1016/j.vaccine.2017.06.030.
44. Yoon D, Lee JH, Lee H, et al. Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study. BMJ (Clinical research ed) 2021; 372: m4931. 2021/01/31. DOI: 10.1136/bmj.m4931.
45. Willame C, Gadroen K, Bramer W, et al. Systematic Review and Meta-analysis of Postlicensure Observational Studies on Human Papillomavirus Vaccination and Autoimmune and Other Rare Adverse Events. The Pediatric infectious disease journal 2020; 39: 287-293. 2019/12/27. DOI: 10.1097/inf.0000000000002569.
46. Rosillon D, Willame C, Tavares Da Silva F, et al. Meta-analysis of the risk of autoimmune thyroiditis, Guillain-Barré syndrome, and inflammatory bowel disease following vaccination with AS04-adjuvanted human papillomavirus 16/18 vaccine. Pharmacoepidemiology and drug safety 2020; 29: 1159-1167. 2020/06/26. DOI: 10.1002/pds.5063.
47. Chen Y, Zhang J, Chu X, et al. Vaccines and the risk of Guillain-Barré syndrome. European journal of epidemiology 2020; 35: 363-370. 2019/12/21. DOI: 10.1007/s10654-019-00596-1.
48. Haber P, Sejvar J, Mikaeloff Y, et al. Vaccines and Guillain-Barre syndrome. Drug Saf 2009; 32: 309-323. 2009/04/25. DOI: 10.2165/00002018-200932040-00005.
49. Klein NP, Lewis N, Goddard K, et al. Surveillance for Adverse Events After COVID-19 mRNA Vaccination. JAMA 2021; 326: 1390-1399. DOI: 10.1001/jama.2021.15072.
50. Patone M, Handunnetthi L, Saatci D, et al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nature medicine 2021; 27: 2144-2153. 2021/10/27. DOI: 10.1038/s41591-021-01556-7.
51. Centers for Disease Control and Prevention. February 2024 ACIP Meeting. In: Meeting of the Advisory Committee on Immunization Practices (ACIP) Atlanta, GA, February 28-29, 2024 2024.
52. Centers for Disease Control and Prevention. June 2024 ACIP Meeting. In: Meeting of the Advisory Committee on Immunization Practices (ACIP) Atlanta, GA, June 26-28, 2024 2024.
53. Yuki N and Hartung HP. Guillain-Barre syndrome. N Engl J Med 2012; 366: 2294-2304. 2012/06/15. DOI: 10.1056/NEJMra1114525.
54. Mizoguchi K. Anti-GQ1b IgG antibody activities related to the severity of Miller Fisher syndrome. Neurological research 1998; 20: 617-624. 1998/10/24.
55. Rees JH, Soudain SE, Gregson NA, et al. Campylobacter jejuni infection and Guillain-Barre syndrome. N Engl J Med 1995; 333: 1374-1379. 1995/11/23. DOI: 10.1056/nejm199511233332102.
56. Tam CC, O’Brien SJ, Petersen I, et al. Guillain-Barre syndrome and preceding infection with campylobacter, influenza and Epstein-Barr virus in the general practice research database. PloS one 2007; 2: e344. 2007/04/05. DOI: 10.1371/journal.pone.0000344.