Identifying adverse event clusters and treatment effects in randomised trials using latent class analysis: an application in the COV-BOOST trial

Abstract Background Randomised controlled trials (RCTs) are essential for evaluating treatment efficacy and safety, particularly in vaccine trials, where adverse events are systematically collected and assessed. The high volume of reported adverse events often presents challenges in discerning meaningful associations between treatments and adverse events. Traditional analytical approaches rely on multiple pairwise treatment comparisons of individual adverse events, which can be difficult to interpret. This study explores the use of latent class analysis (LCA) to identify adverse event profiles and estimates the average treatment effects (ATE) for these in an RCT setting. Methods Data from the COV-BOOST trial (ISRCTN registration 73765130), which assessed the safety and efficacy of seven COVID-19 booster vaccines, was used. This trial monitored a predefined set of 17 adverse events, graded by severity, over a 7-day period following immunisation. LCA was applied to classify participants into adverse event subgroups based on shared event profiles. After identifying these classes, the ATE was estimated for each identified adverse event profile to quantify the causal impact of different vaccine boosters. This was achieved by regressing treatment on the latent adverse event class membership outcome. Results Fatigue, pain, and headache were commonly reported adverse events across all vaccine arms. LCA identified three distinct adverse event profiles among participants: (class 1) minimal AEs, (class 2) mild AEs, and (class 3) severe AEs reports. Four vaccines, ChAd after BNT/BNT primer, Ad26, CVn, and MOD after both primer vaccines, were associated with higher reactogenicity, with most recipients falling into class 2 or 3. Conclusion This study demonstrates the utility of LCA in identifying adverse event profiles within an RCT and uniquely integrates the latent adverse event class membership of participants as an outcome for ATE estimation. By examining the varying effects of booster vaccines in the COV-BOOST trial, this method advances the understanding of these vaccines’ safety. The successful application of this innovative approach in this study could pave the way for its adoption by researchers in future clinical trials across various medical domains. More broadly, integrating LCA with ATE estimation provides a novel framework for enhancing vaccine pharmacovigilance and improving safety assessments for medical interventions.