Serious adverse events (SAEs), including seizures and epilepsy AEs, occur in some individuals following vaccination. AEs and SAEs are referred to as AEs following immunization (AEFI). Epilepsy is a neurological disorder that causes recurring seizures. In a given population, observed AEFIs post-vaccination will be represented by a combination of background AEs and (when they occur) vaccine-induced AEs.

Vaccines provide protection against multiple infectious organisms with the risks of SAEs considered in the context of benefits for each vaccine. Two different vaccines targeting the same organism(s) may differ in vaccine type, vaccine components, excipients, and possible manufacturing contaminants; the risks of SAEs for these vaccines may be similar or different.

With respect to epilepsy SAEs, some vaccines and vaccine combinations have been reported more than others. In a five-year retrospective observational study, of the first 245 status epilepticus hospitalizations with immunization records, 14% were vaccine-proximate of which 18 of 35 (51.4%) followed dose-1 measles-mumps-rubella (MMR) vaccine given concomitantly with Haemophilus influenzae type b and meningococcal C conjugate combined vaccine (Hib-MenC), 12 of 35 (34.3%) followed diphtheria-tetanus-acellular pertussis, inactivated polio, H. influenzae type b and hepatitis B combination (DTaP-IPV-Hib-HBV) vaccine in combination with 13-valent pneumococcal conjugate vaccine (PCV13) with 11 of these 12 also given in combination with rotavirus vaccine (RSV), 3 of 35 (8.5%) followed dose-2 MMR-varicella (MMRV) vaccine, 1 of 35 (2.8%) followed Hepatitis A vaccine (HAV), and 1 of 13 (2.8%) followed Varicella zoster vaccine [1]; status epilepticus most commonly occurred with 0–1 days following vaccination or 8–11 days following MMR containing vaccines [1]. Reported SAEs may reflect possible associations above background population frequencies for some vaccines.

One rare type of epilepsy is known to be associated with epilepsy AEFIs triggered by immunization; children with severe myoclonic epilepsy of infancy (Dravet syndrome) can experience epilepsy AEs following vaccination [2]. Mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene have been observed in 70% of these children [3]. The SCN1A gene encodes a type I voltage-gated sodium channel (Nav 1.1) involved in neural activity [3, 4]. Mutations in the Nav 1.1 channels also cause generalized epilepsy with febrile seizures plus (GEFS+) in older children [4, 5]. In one study, Dravet syndrome patients represented only 2.5% of children with seizures following vaccinations in the first year of life [6]. Protocadherin 19 (PCDH19) [7], gamma-aminobutyric acid type A receptor subunit gamma 2 (GABRG2) [8], and homozygous SCN1B mutations [9] have also been identified (reviewed [10]) in Dravet patients. Note that PCDH19 mutations are associated with either epilepsy with mental retardation limited to females (EFMR) or rarely Dravet syndrome [7]. The currently accepted medical consensus is that aside from children with Dravet syndrome, there are no associations between vaccination and epilepsy AEFIs [11].

Pyrexia (fever) is a common AEFI associated with immunization [12]. Immunizations can cause high fever and rarely febrile seizure AEFIs [13]. Generally considered benign, febrile seizure is the most common convulsive event during childhood [14]. In a study of 109 febrile seizure patients, 6 were diagnosed with subsequent epilepsy 5 to 46 months later of which 3 of 15 had delayed vaccination status (P = 0.03) [15]. In a study of children experiencing seizures, 1.4% of these seizures followed within two weeks of an immunization procedure [16]; all but one of these seizures were associated with fever, often high [16]. One combination vaccine, DTaP-IPV-Hib, was associated with an increased risk of febrile seizures on the day of the first 2 vaccinations [17]. Febrile seizures represent a rare SAE.

When SAE associations exist, it is possible for a vaccine component, excipient, or manufacturing contaminant to be the triggering or causative agent(s). Activation of innate immune responses by Toll-like receptors (TLRs) may play a key role in the etiopathology of epilepsy and convulsive disorders [18]. TLRs are an important family of receptors in the defense against microbes [19]. The TLR4 receptor is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria [20]. The bacterial endotoxin lipopolysaccharide enhances seizure susceptibility in mice [21]. One study suggests that vaccination triggers, rather than causes seizures AEFIs [22].

AEFIs are tracked by different countries. In the United States, the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA), co-sponsor the Vaccine AEs Reporting System (VAERS) database [23]. Medical professionals and vaccinees can report AEFIs to VAERS. The AEFIs reported to VAERS represent a subset of the actual AEFIs experienced by vaccinees (i.e., population samples). Herein, VAERS AEFIs for epilepsy and seizure AEFIs are retrospectively analyzed. This retrospective study examines these AEFIs in the context of two competing hypotheses:

Hypothesis 1—vaccinations are not associated with or trigger epilepsy AEFIs except for individuals with Dravet syndrome.

Hypothesis 2—one or more vaccine manufacturing contaminants, or possibly in some instances vaccine excipients or components, are associated with triggering epilepsy AEFIs for some vaccinees.

Herein, multiple SAE associations are observed for (1) multiple vaccines for infants and (2) human papillomavirus (HPV) vaccines for teenagers and young adults. Statistically different normalized epilepsy AEFIs normalized frequencies from different manufacturers are suggestive of differences resulting from possible manufacturing contaminants (e.g., endotoxins). Predicted manufacturing contaminants (e.g., endotoxins) are consistent with the observed associations with multiple vaccines SAE associations. These observed associations warrant further investigations.

Focusing on epilepsy, the VAERS database [23] was retrospectively examined for the AEs designated by the following Medical Dictionary for Regulatory Activities (MedDRA) codes [24] [MedDRA^® the Medical Dictionary for Regulatory Activities terminology is the international medical terminology developed under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)]: epilepsy, infant spasms, petit mal epilepsy, seizure (newer MedDRA code) or convulsion (recently discontinued in VAERS), severe myoclonic epilepsy of infancy (Dravet syndrome), status epilepticus, and generalised tonic-clonic seizure. The downloaded VAERS data includes all AEFIs reported from 1990 to April 26, 2024.

The Python program vaers_reports.py [25] was developed for retrospective analysis of the VAERS data files VAERSDATA, VAERSSYMPTOMS, and VAERSVAX for the years 1990 to 2024 and nondomestic. The vaers_reports.py program tallies vaccine AEFIs by vaccine, day of onset, age, gender, and co-administered vaccines. The vaers_reports.py program takes a list of one or more AE names as input. Note that VAERS vaccine codes are presented in the results and also figures.

In statistics, Pearson correlation is a statistical method that measures the similarity or correlation between two data sets. Herein, Pearson correlation is applied to compare the patterns of AEFI normalized frequencies for multiple vaccines between two AEs. Microsoft Excel was used to calculate Pearson correlations and prepare figures. A Chi-square test is a hypothesis testing method for checking if observed frequencies in one or more categories match expected frequencies. Herein, the Chi-square test is used to examine if the AEFI normalized frequencies (observed AEFI/vaccine AEFIs * constant) are consistent for one AE between two vaccines. Chi-square calculations were performed with an online Chi-square 2 × 2 calculator [26].

The current accepted medical consensus is consistent with hypothesis 1 with no associations of epilepsy AEs with vaccinations (aside from trigger event associations for children with Dravet syndrome) [11]. For some vaccines, the retrospective AEFIs in VAERS for epilepsy are discordant with hypothesis 1; some vaccines (6VAX-F, HPV2, PNC10, and others) have high epilepsy AEFI normalized frequencies above background levels observed for other vaccines. For the same vaccine from different manufacturers, the normalized frequencies are highly discordant with statistical significance (Figure 2). In addition, epilepsy AEFIs associated with HPV vaccinations in older individuals are unlikely vaccinees with Dravet syndrome. Hence, hypothesis 1 is rejected.

Many of the vaccines associated with higher epilepsy AEFIs normalized frequencies (Figure 1) are also associated with generalized tonic-clonic seizure, petit mal epilepsy, status epilepticus, infant spasms, and seizure AEFIs (Figures 4, 5 and 6). While shared vaccine excipients have not been excluded, possible shared manufacturing contaminants are more likely associated with these observed vaccine AEFI associations. While inclusion of bacterial vaccine components [Bordetella pertussis (DTaP, 6VAX-F, etc.), H. influenzae (Hib), Streptococcus pneumoniae (PNC), Neisseria meningitidis (meningococcal—MenB), etc.] is a possible factor, large differences in normalized frequencies for the same vaccine from different manufacturers (Figure 2) supports possible shared manufacturing contaminants as the more probable risk factor. Note that infants age 0 have higher susceptibility to these risks than older infants age 1 (Figure 3).

Generalized tonic-clonic seizure AEFIs, petit mal epilepsy AEFIs, and status epilepticus AEFIs exhibit similar associations as epilepsy AEFIs for multiple vaccines, with the highest normalized frequencies for 6VAX-F for these three AEFIs (Figure 4). Forty-six seizure AEFI normalized frequencies (Figure 6) are above 1,000 per 100,000 VAERS reports.