Assessment of Neurological and Immunological Adverse Events Following Childhood Pneumococcal Vaccination: a Population-Based Self-Controlled Risk Interval Analysis

Background: Pneumococcal conjugate vaccine (PCV) confers protection against invasive pneumococcal diseases caused by different serotypes of streptococcus pneumoniae. While generally considered safe, several safety signals were flagged during post-licensure surveillance of PCVs. Of those, only Kawasaki disease has been exploited extensively for its association with PCV, whereas there is a paucity of data on the others that are rare but potentially serious adverse events (AEs).

Objectives: To evaluate the association between AEs of interest and 3-dose series of PCV administered at 2, 4 and 6 months of age.

Methods: We conducted a population-based self-controlled risk interval analysis using the National Health Insurance Database linked with Korea Immunization Registry Information System. Infants born between 2018 and 2021 and received at least one dose of 10- or 13-valent PCV were identified, and only those who had outcome during risk or control interval were included in the analysis. The outcomes included 2 neurological (encephalopathy and febrile seizure) and 4 immunological AEs (anaphylaxis, asthma, thrombocytopenia and Kawasaki disease), restricted to diagnosis at primary or secondary position. For sub-acute outcomes (asthma, encephalopathy, thrombocytopenia, Kawasaki disease), we assigned Days 1-28 and 29-56 post-vaccination as the risk and control intervals, respectively. For acute outcomes, we assigned shorter intervals and washout period of 7 days between the intervals, corresponding to Days 0-2 and 10-12 for anaphylaxis and Days 0-8 and 16-23 for febrile seizure. We used conditional Poisson regression model to estimate the incidence rate ratios (IRRs), adjusted for age in weeks, and corresponding 95% confidence interval (CI) comparing the outcomes in the risk and control intervals.

Results: Among 8731 out of 1,114,096 infants included in the analysis, the mean (standard deviation) age at dose 1 was 10.0 (2.5) weeks, 58.2% were male, and 85.2% received 13-valent PCV. There were no significant association between the AEs and PCV except for febrile seizure, for which there were 408 (56.0%) cases in the risk interval, corresponding to IRR of 1.27 (95% 1.10-1.47). When stratified by dose number, the association remained significant for dose 1 (IRR 1,50, 95% CI 1.16-1.94) and dose 2 (1.45, 1.11-1.89), but not for dose 3 (0.96, 0.76-1.23).

Conclusions: In this study, PCVs were not associated with major neurological and immunological AEs. Despite the small increased risk of febrile seizure observed following PCVs, absolute number of cases were small. Besides, febrile seizures are generally self-limiting with good prognosis, and should not discourage parents or caregivers from vaccinating their children.