Do Vaccines Cause Seizures?

Conclusion | Epidemiological Evidence | Proposed Biological Mechanism | Archives | References


Fever is a common symptom of many natural infections, including bacteria such as diphtheria, pertussis, meningococcus and pneumococcus, and viruses such as hepatitis A, hepatitis B, influenza, measles mumps, rubella, polio, rotavirus and varicella. Fever is associated with febrile seizures in infants. Thus, many vaccines prevent fever and febrile seizures by protecting against natural infections.

However, all vaccines that cause fever in young children also have a small inherent risk of causing febrile seizures. The first dose of measles-containing vaccines can rarely cause febrile seizures in infants and young children 7-10 days after vaccination, at an estimated rate of 1 event per 2,500 doses of MMR or 1 event per 1,250 doses of MMRV (ProQuad). Influenza and pneumococcal conjugate vaccines when administered separately can very rarely cause febrile seizures in infants and young children in the 24 hours after vaccination, at an estimated rate of 5 events per 100,000 doses in the U.S. The risk of febrile seizures is increased when influenza and pneumococcal conjugate vaccines are given simultaneously, to an estimated rate of 17.5 per 100,000 doses. The DTaP-IPV-Hib combination vaccine in use in Denmark can very rarely cause febrile seizures in infants and young children, at an estimated rate of less than 4 per 100,000 doses. Whole-cell DTP vaccine did cause febrile seizures, but is no longer used in the United States. Vaccines currently routinely recommended to the general population in the U.S.* have not been shown to cause persistent epilepsy or infantile spasms.

Febrile seizures are a common and typically benign childhood condition, occurring in 2-5% of children at some point during their first five years of life. Febrile seizures have an estimated background incidence of 240–480 per 100,000 person-years in children under five years, although this varies considerably by age, genetics, co-morbidities and environmental risk factors. There are no long-term effects of simple febrile seizures, with the possible exception of an increased risk of recurrence [1-4].

Considering the benign nature of simple febrile seizures, the rarity of vaccine-induced febrile seizures and the relative frequency of fever related to natural infection particularly among young children, the benefits of vaccination greatly outweigh the minimal risk of vaccine complications.

Epidemiological Evidence

Between 5% and 15% of children receiving the first dose of measles-containing vaccines develop a transient fever > 103°F, 7-12 days after the first dose. Febrile seizures occur at a rate of about 1 per 2,500 doses of MMR. The risk is increased to approximately 1 per 1,250 doses if the first dose is the combination vaccine MMRV. However, there is no increased risk of fever or febrile seizures in children receiving their second dose of measles-containing vaccine, including both MMR and MMRV, between 4 and 6 years of age [5, 6].

Febrile seizures were estimated to occur at a rate of 17.5 per 100,000 doses in children aged 6-59 months after receiving concomitant trivalent inactivated influenza vaccine (TIV) and 13-valent pneumococcal conjugate vaccine (abbreviation: PCV13; trade name: Prevnar13®); lower rates of 4.9 per 100,000 doses and 5.3 per 100,000 doses were estimated in children who received TIV without concomitant PCV13 and in children who received PCV13 without concomitant TIV, respectively. However, these risk differences varied substantially with age due to the age-dependent background rates of febrile seizures, with the highest estimates at 16 months and the lowest at 59 months [4].

Nine methodologically sound, controlled epidemiological studies have all found an increased risk of seizures 7-14 days after MMR vaccination [7-15]. The MMRV combination vaccine has a higher risk of febrile convulsions than simultaneous yet separate administration of MMR and varicella vaccine (Varivax®) [16-21]. Delaying MMR or MMRV vaccines past 15 months of age results in a higher risk of seizures than vaccinating according to the recommended schedule [22, 23].

Aside from the CSL Biotherapies trivalent vaccine licensed in Australia in 2010 [24, 25], influenza vaccines have generally not been associated with seizures. Five methodologically sound, controlled epidemiological studies found no statistically significant association between seizures and influenza vaccination [26-30]. However, a large Vaccine Safety Datalink study of children under 5 years of age did find a small increased risk of seizures after TIV (incidence rate ratio 2.4; 95% CI 1.2-4.7), as well as a similar increased risk after PCV13 (IRR 2.5; 95% CI 1.3-4.7) and an even further increased risk after receiving both vaccines simultaneously (IRR 5.9; 95% CI 3.1-11.3) [4].

The 2012 report by the Institute of Medicine (IOM) [31], now called the National Academy of Medicine (NAM), did not find convincing evidence of an association between seizures and varicella, DTaP or hepatitis B vaccines [12, 32-35]. A large cohort study published since this report found a small increased risk of febrile seizure after the first two doses of the DTaP-IPV-Hib combination vaccine in Denmark, with an absolute risk of less than 4 per 100,000 vaccinations [36]. Two large Vaccine Safety Datalink studies published since the 2012 IOM report found no association between seizures and the DTaP-IPV combination vaccine (Kinrix®) [37] or quadrivalent HPV vaccine (Gardasil®) [38].

A case-control study reviewed in the 2012 IOM report did not find convincing evidence of an association between infantile spasms and the tetanus and diphtheria toxoid vaccines [39], and the report found no relevant studies of quality in the literature assessing an association between infantile spasms and pertussis vaccine [31]. No relevant studies of quality examining infantile spasms and vaccination have been published since this report.

Proposed Biological Mechanism

Immunization may induce fever through the release of cytokines from inflammatory cells, and fever is associated with febrile seizures [31]. Although an interaction of genetics, brain maturity, and fever is hypothesized, the pathophysiology of febrile seizures is largely unknown [3]. The pathogenesis may be explained by alteration of brain ion channel function due to change in temperature [40, 41], modification of neuronal excitability [42] or fever-induced respiratory alkalosis [43]. Studies have shown that genetic susceptibility plays an important role in the pathogenesis of febrile seizures, and various loci have been mapped on different chromosomes in individuals with febrile seizures [44-57]. For well-studied vaccines such as influenza vaccines, increases in reactogenicity have been shown to be associated with differences in manufacturing procedures [58-60].


1. (AAP) AAoP. Neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics 2011;127:389-94.
2. (AAP) AAoP. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics 2008;121:1281-6.
3. Bonhoeffer J, Menkes J, Gold MS, et al. Generalized convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004;22:557-62.
4. Tse A, Tseng HF, Greene SK, Vellozzi C, Lee GM. Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011. Vaccine 2012;30:2024-31.
5. Epidemiology and Prevention of Vaccine-Preventable Diseases. Washington D.C.: Centers for Disease Control and Prevention; 2015.
6. Vaccine Information Statements (VIS). 2015, at
7. Barlow WE, Davis RL, Glasser JW, et al. The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine. The New England journal of medicine 2001;345:656-61.
8. Farrington P, Pugh S, Colville A, et al. A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines. Lancet 1995;345:567-9.
9. Chen RT, Glasser JW, Rhodes PH, et al. Vaccine Safety Datalink project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team. Pediatrics 1997;99:765-73.
10. Griffin MR, Ray WA, Mortimer EA, Fenichel GM, Schaffner W. Risk of seizures after measles-mumps-rubella immunization. Pediatrics 1991;88:881-5.
11. Vestergaard M, Hviid A, Madsen KM, et al. MMR vaccination and febrile seizures: evaluation of susceptible subgroups and long-term prognosis. Jama 2004;292:351-7.
12. Andrews N, Stowe J, Miller E, Taylor B. Post-licensure safety of the meningococcal group C conjugate vaccine. Hum Vaccin 2007;3:59-63.
13. Miller E, Andrews N, Stowe J, Grant A, Waight P, Taylor B. Risks of convulsion and aseptic meningitis following measles-mumps-rubella vaccination in the United Kingdom. Am J Epidemiol 2007;165:704-9.
14. Ward KN, Bryant NJ, Andrews NJ, et al. Risk of serious neurologic disease after immunization of young children in Britain and Ireland. Pediatrics 2007;120:314-21.
15. Gold M, Dugdale S, Woodman RJ, McCaul KA. Use of the Australian Childhood Immunisation Register for vaccine safety data linkage. Vaccine 2010;28:4308-11.
16. Jacobsen SJ, Ackerson BK, Sy LS, et al. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine 2009;27:4656-61.
17. Klein NP, Fireman B, Yih WK, et al. Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures. Pediatrics 2010;126:e1-8.
18. Klopfer SO, Stek JE, Petrecz M, et al. Analysis of safety data in children after receiving two doses of ProQuad(R) (MMRV). Vaccine 2014;32:7154-60.
19. Macartney KK, Gidding HF, Trinh L, et al. Febrile seizures following measles and varicella vaccines in young children in Australia. Vaccine 2015;33:1412-7.
20. MacDonald SE, Dover DC, Simmonds KA, Svenson LW. Risk of febrile seizures after first dose of measles-mumps-rubella-varicella vaccine: a population-based cohort study. Cmaj 2014;186:824-9.
21. Schink T, Holstiege J, Kowalzik F, Zepp F, Garbe E. Risk of febrile convulsions after MMRV vaccination in comparison to MMR or MMR+V vaccination. Vaccine 2014;32:645-50.
22. Hambidge SJ, Newcomer SR, Narwaney KJ, et al. Timely versus delayed early childhood vaccination and seizures. Pediatrics 2014;133:e1492-9.
23. Rowhani-Rahbar A, Fireman B, Lewis E, et al. Effect of age on the risk of Fever and seizures following immunization with measles-containing vaccines in children. JAMA Pediatr 2013;167:1111-7.
24. Armstrong PK, Dowse GK, Effler PV, et al. Epidemiological study of severe febrile reactions in young children in Western Australia caused by a 2010 trivalent inactivated influenza vaccine. BMJ Open 2011;1:e000016.
25. Kelly HA, Skowronski DM, De Serres G, Effler PV. Adverse events associated with 2010 CSL and other inactivated influenza vaccines. Med J Aust 2011;195:318-20.
26. France EK, Glanz JM, Xu S, et al. Safety of the trivalent inactivated influenza vaccine among children: a population-based study. Archives of pediatrics & adolescent medicine 2004;158:1031-6.
27. Hambidge SJ, Glanz JM, France EK, et al. Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old. Jama 2006;296:1990-7.
28. Goodman MJ, Nordin JD, Harper P, Defor T, Zhou X. The safety of trivalent influenza vaccine among healthy children 6 to 24 months of age. Pediatrics 2006;117:e821-6.
29. 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. Am J Epidemiol 2010;171:177-88.
30. Stowe J, Andrews N, Bryan P, Seabroke S, Miller E. Risk of convulsions in children after monovalent H1N1 (2009) and trivalent influenza vaccines: a database study. Vaccine 2011;29:9467-72.
31. Institute of Medicine. In: Stratton K, Ford A, Rusch E, Clayton EW, eds. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2012.
32. Black S, Shinefield H, Ray P, et al. Postmarketing evaluation of the safety and effectiveness of varicella vaccine. The Pediatric infectious disease journal 1999;18:1041-6.
33. Lewis E, Shinefield HR, Woodruff BA, et al. Safety of neonatal hepatitis B vaccine administration. The Pediatric infectious disease journal 2001;20:1049-54.
34. Huang WT, Gargiullo PM, Broder KR, et al. Lack of association between acellular pertussis vaccine and seizures in early childhood. Pediatrics 2010;126:263-9.
35. Yih WK, Nordin JD, Kulldorff M, et al. An assessment of the safety of adolescent and adult tetanus-diphtheria-acellular pertussis (Tdap) vaccine, using active surveillance for adverse events in the Vaccine Safety Datalink. Vaccine 2009;27:4257-62.
36. Sun Y, Christensen J, Hviid A, et al. Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type B. Jama 2012;307:823-31.
37. Daley MF, Yih WK, Glanz JM, et al. Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine. Vaccine 2014;32:3019-24.
38. Gee J, Naleway A, Shui I, et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011;29:8279-84.
39. Goodman M, Lamm SH, Bellman MH. Temporal relationship modeling: DTP or DT immunizations and infantile spasms. Vaccine 1998;16:225-31.
40. Shibasaki K, Suzuki M, Mizuno A, Tominaga M. Effects of body temperature on neural activity in the hippocampus: regulation of resting membrane potentials by transient receptor potential vanilloid 4. The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27:1566-75.
41. Thomas EA, Hawkins RJ, Richards KL, Xu R, Gazina EV, Petrou S. Heat opens axon initial segment sodium channels: a febrile seizure mechanism? Ann Neurol 2009;66:219-26.
42. Balosso S, Maroso M, Sanchez-Alavez M, et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain : a journal of neurology 2008;131:3256-65.
43. Schuchmann S, Schmitz D, Rivera C, et al. Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nature medicine 2006;12:817-23.
44. Wallace RH, Berkovic SF, Howell RA, Sutherland GR, Mulley JC. Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21. Journal of medical genetics 1996;33:308-12.
45. Johnson EW, Dubovsky J, Rich SS, et al. Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest. Human molecular genetics 1998;7:63-7.
46. Peiffer A, Thompson J, Charlier C, et al. A locus for febrile seizures (FEB3) maps to chromosome 2q23-24. Ann Neurol 1999;46:671-8.
47. Nakayama J, Hamano K, Iwasaki N, et al. Significant evidence for linkage of febrile seizures to chromosome 5q14-q15. Human molecular genetics 2000;9:87-91.
48. Nakayama J, Fu YH, Clark AM, et al. A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. Ann Neurol 2002;52:654-7.
49. Nabbout R, Prud'homme JF, Herman A, et al. A locus for simple pure febrile seizures maps to chromosome 6q22-q24. Brain : a journal of neurology 2002;125:2668-80.
50. Nakayama J, Yamamoto N, Hamano K, et al. Linkage and association of febrile seizures to the IMPA2 gene on human chromosome 18. Neurology 2004;63:1803-7.
51. Hedera P, Ma S, Blair MA, et al. Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22. Epilepsia 2006;47:1622-8.
52. Audenaert D, Van Broeckhoven C, De Jonghe P. Genes and loci involved in febrile seizures and related epilepsy syndromes. Human mutation 2006;27:391-401.
53. Poduri A, Wang Y, Gordon D, et al. Novel susceptibility locus at chromosome 6q16.3-22.31 in a family with GEFS+. Neurology 2009;73:1264-72.
54. Schlachter K, Gruber-Sedlmayr U, Stogmann E, et al. A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures. Neurology 2009;72:974-8.
55. Saghazadeh A, Mastrangelo M, Rezaei N. Genetic background of febrile seizures. Reviews in the neurosciences 2014;25:129-61.
56. Feenstra B, Pasternak B, Geller F, et al. Common variants associated with general and MMR vaccine-related febrile seizures. Nature genetics 2014;46:1274-82.
57. Verbeek NE, Jansen FE, Vermeer-de Bondt PE, et al. Etiologies for seizures around the time of vaccination. Pediatrics 2014;134:658-66.
58. Blyth CC, Currie AJ, Wiertsema SP, et al. Trivalent influenza vaccine and febrile adverse events in Australia, 2010: clinical features and potential mechanisms. Vaccine 2011;29:5107-13.
59. Rockman S, Dyson A, Koernig S, et al. Evaluation of the bioactivity of influenza vaccine strains in vitro suggests that the introduction of new strains in the 2010 Southern Hemisphere trivalent influenza vaccine is associated with adverse events. Vaccine 2014;32:3861-8.
60. Rockman S, Becher D, Dyson A, et al. Role of viral RNA and lipid in the adverse events associated with the 2010 Southern Hemisphere trivalent influenza vaccine. Vaccine 2014;32:3869-76.