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.
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. Nine methodologically sound, controlled epidemiological studies have all found an increased risk of seizures 7-14 days after MMR vaccination [5-13]. A 2016 summary of 23 post-licensure clinical trials and a 2015 meta-analysis both confirmed these findings [14, 15]. The MMRV combination vaccine (ProQuad®) has a higher risk of febrile convulsions than simultaneous yet separate administration of MMR and varicella vaccine (Varivax®) [16-21]. Febrile seizures occurred at a rate of 26.4 per 1000 person-years after MMR and 84.6 per 1,000 person-years after MMRV in the 7-10 days after vaccination . There is no increased risk of fever or febrile seizures in children receiving their second dose of measles-containing vaccine at 4 to 6 years of age, whether given MMR or MMRV [22-24]. Delaying MMR or MMRV vaccines past 15 months of age results in a higher risk of seizures than vaccinating according to the recommended schedule [25, 26].
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 .
Aside from the CSL Biotherapies trivalent vaccine licensed in Australia in 2010 [27-29], influenza vaccines have generally not been associated with seizures. Six methodologically sound, controlled epidemiological studies found no statistically significant association between seizures and influenza vaccination [30-35]. However, a large Vaccine Safety Datalink (VSD) 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) . Another VSD study found an increased risk of febrile seizures following concomitant administration of TIV and PCV13 (relative risk 5.3; 95% CI 1.87-14.75) . A self-controlled risk interval analysis found that although TIV administered by itself had no increased risk of febrile seizures, risk of febrile seizures on the two days following vaccination increased when TIV was administered simultaneously with either PCV (IRR 3.50; 95% CI 1.13-10.85) or DTaP-containing vaccines (IRR 3.50; 95% CI 1.52-8.07). This concomitant administration led to a small absolute risk of 30 excess febrile seizures per 100,000 persons vaccinated . In addition, a study of 226,889 Norwegian children found a twofold increased risk of febrile seizures in the 1-3 days after pH1N1 vaccination . However, the same study also found a tenfold increased risk of febrile seizures in the 1-3 days after diagnosis of pH1N1 infection.
The 2012 report by the Institute of Medicine (IOM) , 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 [10, 40-43]. 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 . Two large VSD studies published since the 2012 IOM report found no association between seizures and the DTaP-IPV combination vaccine (Kinrix®)  or quadrivalent HPV vaccine (Gardasil®) . A retrospective observational study of California infants had 5 cases of seizures considered related to vaccine receipt out of 46,486 doses of DTaP-IPV/Hib vaccine administered . A large VSD study found that vaccination in children 3-5 months of age was associated with increased risk of febrile seizures (incidence rate ratio: 23; 95% CI 5.13-100.8) on the day of and the day after vaccination, leading to a small attributable risk of 3.92 febrile seizures per 100,000 children vaccinated .
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 , and the report found no relevant studies of quality in the literature assessing an association between infantile spasms and pertussis vaccine . 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 . Although an interaction of genetics, brain maturity, and fever is hypothesized, the pathophysiology of febrile seizures is largely unknown . The pathogenesis may be explained by alteration of brain ion channel function due to change in temperature [50, 51], modification of neuronal excitability  or fever-induced respiratory alkalosis . 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 [54-67]. For well-studied vaccines such as influenza vaccines, increases in reactogenicity have been shown to be associated with differences in manufacturing procedures [68-70].
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