Serious adverse events following human papillomavirus vaccination: A systematic review and meta-analysis of post-marketing evidence

Human papillomavirus (HPV) vaccines are a critical tool in cancer prevention, yet concerns about serious adverse events (SAEs) have fueled public hesitancy and constrained vaccination uptake. This systematic review aimed to determine the proportion of adverse events that were SAEs, rate of SAEs following HPV vaccination and their association from post-marketing observational studies. We conducted a search in PubMed, EMBASE, and Web of Science databases in March 2025. Studies published in English reporting SAEs after HPV vaccination from post-licensure studies or surveillance were included. Of the 258 identified records, 24 articles were included in the systematic review: 15 in the meta-analysis and 9 in the narrative synthesis. Among the studies included in the meta-analysis, four found no SAEs; the pooled proportion of adverse events that were SAEs was 3.67% (95% confidence interval, CI: 1.19%, 7.30%), I2 = 99.73%. The pooled rate of SAEs in 14 studies that reported total number of doses distributed was 0.04 (95% CI: 0.00, 0.35) per 1000 doses, I2 = 99.98%. No consistent evidence of any increased risk of SAEs with HPV vaccination was found in the nine studies included in the narrative synthesis. However, an increased risk of celiac disease was observed, likely due to diagnostic unmasking rather than a causal association, warranting further investigation. Our findings provide evidence that SAEs remain rare following HPV vaccination. Nevertheless, continued surveillance and improved standardization of SAE definition and reporting are essential to strengthen post-marketing safety monitoring and counteract vaccine misinformation.