A broad assessment of rotavirus vaccine safety in infants in Korea: Insights from a data-driven signal detection approach

In light of the widespread use of rotavirus vaccines, there is a pressing need to perform thorough, large-scale surveillance to actively monitor safety. This study aimed to identify potential adverse events following rotavirus vaccination in infants. Using a nationwide linked database of the national immunization registry and health insurance claims data, we identified infants vaccinated with the first dose of rotavirus vaccine between January 2016 and October 2022. The self-controlled tree-temporal scan statistics method analyzed all incident diagnoses recorded within 56 days post-vaccination and evaluated all temporal risk windows. Among 1,720,778 rotavirus vaccine recipients 64,752 infants contributed to the analysis, yielding 72,970 incident diagnoses. Of these, 28 clusters were categorized as known adverse drug reactions (ADRs), including infection following immunization (Days 1-2, <i>p</i><.001), viral infection (Days 1-5, <i>p</i><.001), urticaria and erythema (Days 3-9, <i>p</i><.001), acute upper respiratory infections (Days 28-42, <i>p</i><.001), and pneumonia (Days 9-19 or 28-42, <i>p</i><.001). Seventeen clusters were classified as ADR-related events, such as the ones clinically related to ADR or lower-level diagnostic codes of ADR. The remaining 26 clusters were classified as signals, including sepsis (Days 1-20, <i>p</i><.001), meningitis (Days 1-23, <i>p</i><.001), liver disease (Days 4-11, <i>p</i><.001), and tubulo-interstitial nephritis (Days 11-38, <i>p</i><.001). A cluster of intussusceptions was only found in monovalent vaccine-stratified analysis (Days 5-8, <i>p</i> = 0.005). This study confirmed known ADRs following rotavirus vaccination, while identifying potential safety signals requiring further investigation. These findings emphasize the importance of active vaccine surveillance and underscore the need for epidemiological studies with validated outcome definitions to confirm causal relationships between rotavirus vaccination and the detected outcomes.