Global impact of hepatitis B vaccination on the risk of hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to synthesize global evidence on the association between hepatitis B virus (HBV) vaccination and incident hepatocellular carcinoma (HCC), including subgroup analyses by country/region, vaccine formulation, and dosing regimen. METHODS: PubMed, Scopus, and Web of Science were searched from inception to July 24, 2025. The study protocol was registered on PROSPERO (ID: 1355073). Studies were eligible if they reported HCC incidence or risk among vaccinated versus unvaccinated populations, included >20 cases, and provided extractable comparative data. Methodological quality was appraised using the National Institutes of Health (NIH) Quality Assessment Tool. Random-effects models (DerSimonian-Laird) were used to pool incidence rate ratios (IRRs) and adjusted relative risks (aRRs), expressed with 95% confidence intervals (CIs). RESULTS: Sixteen studies encompassing over 5 million participants met inclusion criteria. The pooled unadjusted analysis demonstrated a 65% reduction in HCC incidence among vaccinated individuals (IRR =0.35, 95% CI: 0.26-0.47; I2=76.5%). Protection was consistent across subgroups, including males (IRR =0.25, 95% CI: 0.12-0.53) and females (IRR =0.43, 95% CI: 0.20-0.94). The pooled adjusted estimate confirmed a 67% lower risk of HCC (aRR =0.33, 95% CI: 0.24-0.46; I2=83.4%, with substantial between-study heterogeneity). Plasma-derived vaccines were associated with a significantly reduced HCC risk (aRR =0.34, 95% CI: 0.25-0.47), whereas the pooled estimate for recombinant vaccines was directionally consistent but did not reach statistical significance (aRR =0.16, 95% CI: 0.01-3.72), likely reflecting the limited number of contributing studies. Comparable protection was observed with ≥2-dose or ≥3-dose regimens. No study was rated poor in quality; five were good and nine were fair; the two randomized trials were appraised separately using the Cochrane Risk of Bias 2 tool. CONCLUSIONS: HBV vaccination is associated with a significant and durable reduction in HCC risk, independent of demographic, geographic, or vaccine-related factors. These findings are consistent with the view that universal HBV immunization is among the most effective population-level cancer prevention strategies worldwide.