Predictive Profiling of Post-Booster Reactogenicity: Identifying Factors Associated with Adverse Events Following COVID-19 Vaccination

Abstract

COVID-19 booster vaccination remains central to protecting older adults against severe disease;
however, the occurrence and severity of post-booster adverse events vary considerably between
individuals. This prospective observational cohort study evaluated factors associated with post-
booster reactogenicity among adults aged ≥60 years receiving a COVID-19 booster dose. Local and
systemic adverse events were recorded using a structured follow-up form and combined into a
composite adverse-event score as the primary outcome. Candidate predictors, including age, sex,
previous COVID-19 infection, previous significant vaccine reaction, booster-dose interval, diabetes
mellitus, and hypertension, were evaluated using univariable analysis and multivariable linear
regression. Independent predictors were incorporated into a simplified point-based score, and model
performance was assessed by internal validation. Among 500 enrolled participants, 472 (94.4%)
completed follow-up. Injection-site pain was the most frequently reported adverse event (60.6%),
followed by fatigue (51.1%) and headache (41.9%). Female sex, previous COVID-19 infection,
previous significant vaccine reaction, and a shorter booster-dose interval (<6 months) were
independently associated with higher adverse-event scores. Previous significant vaccine reaction
showed the strongest association (β = 0.68; standardized β = 0.25), whereas age, diabetes mellitus,
and hypertension were not independent predictors. The multivariable model explained 34% of the
variance in adverse-event scores (RMSE = 1.12), with 31% explained on internal validation (RMSE =
1.18). A simplified 0–5 point score classified participants into low-, moderate-, and high-risk
categories, with mean predicted scores of 1.2, 2.8, and 4.3, respectively. These findings indicate that
sex, previous infection, prior vaccine-reaction history, and booster-dose interval are associated with
individual differences in post-booster reactogenicity among older adults. Although the proposed score
may support individualized counselling and post-vaccination monitoring, it should be considered
exploratory and requires external validation in larger, independent cohorts before clinical application.