Association between the Rotavirus Vaccine and Intussusception in China: Study Protocol for Target Trial Emulation

Background: Rotavirus vaccines represent a cost-effective and efficacious strategy for the prevention and management of severe rotavirus gastroenteritis, but potential associations of vaccines with intussusception often raise concerns, and this relationship has rarely been reported in China. Methods: This study aims to explicitly emulate a target trial that is consistent with previous randomized controlled trials and subsequently conducts a nested case-control study to evaluate the risk of intussusception within 90 days of rotavirus vaccination. The study will utilize local birth cohorts from 2015 to 2023 across three locations: Ningbo city, Chongqing city, and Jiangsu Province, where the feasibility of accessing electronic healthcare records has been confirmed through a pilot assessment. Cases of suspected intussusception will be identified from various diagnostic settings, including outpatient and inpatient records, imaging, enema records, and surgical reports, adhering to Brighton's criteria for the inclusion of first-occurring cases classified as Brighton certainty level 1. The risk of intussusception will be evaluated via pooled logistic regression methods, adjusting for age, sex, birth season, site, pregnancy exposure, etc . Subgroup analyses will include the postvaccination period, vaccine type, number of doses, and full vaccination. Sensitivity analysis will consider the vaccination day 0, multiple imputation for missing data, propensity score matching, self-controlled analysis, and negative outcome control. Discussion: This is the first, multicenter, large-scale, proactive surveillance study of the risk of intussusception after rotavirus vaccination in China. With the framework of target trial emulation, the nested case-control design would minimize or control relevant bias and confounding in real-world comparative safety studies. This evidence will support the decision of immunization programs in China and contribute to addressing the vaccine hesitancy worldwide.