Exploring Vaccine Side Effects: Why Do Some Children Get Seizure After Measles Vaccination

Despite the tremendous success of vaccination efforts across the globe, outbreaks of vaccine-preventable childhood diseases in communities around the United States are increasing. These localized outbreaks, due in part to decreased vaccination coverage, are likely the result of a public skepticism about the safety of childhood vaccinations.  To help restore trust in the vaccination effort, it is important to understand a vaccine’s full range of side effects. For example, an increased risk of febrile seizure has been associated with a variety of common childhood vaccines, most notably the measles, mumps, and rubella vaccines. Currently, however, the biological cause of vaccination induced febrile seizure (VIFS) remains unclear and little is known as to why only a subset of the vaccine’s recipients is affected.  Towards these goals, we conducted a study to survey the genetic architecture of VIFS following measles vaccination. In total, 274 California residents, 133 of whom experienced febrile seizure post-measles vaccination and 141 matched controls, were genotyped and exome sequenced. Using the analytical software PLINK, 5,757,137 markers were tested for association with VIFS, which highlighted potential genes of interest in VIFS that either regulate neuronal activity or immune system function (rs202194476 in PTPRD, p = 1.6x10-6 ; rs11186481 near SH2D4B, p = 7.7x10-6; and rs56682383 in DPYD, p = 2.4X10-5). We also analyzed exome sequencing data and applied gene-based association testing (via the optimized sequence kernel association test (SKAT-O)) to identify other genes with potential roles in VIFS. This analysis highlighted potential genes of interests with roles in immune system regulation and apoptosis (BATF, p = 6.1x10-6; DDI2, p = 6.5x10-5; NDUFS3, p = 8.9x10-5; DEFB126, p = 2.1x10-5). As the first genotypic and sequencing study of VIFS, this work provides the first detailed look at the underlying genetic architecture of VIFS. As such, it builds the foundation for our understanding of a serious but unexplained side effect of the common measles vaccine, which could not help to restore any lost trust in the safety of vaccination but also potentially work towards a strategy to stratify a patient’s risk for developing VIFS.