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

Introduction

Hepatocellular carcinoma (HCC) ranks among the most lethal malignancies globally, ranking as the third leading cause of cancer mortality and the sixth most commonly diagnosed cancer in 2020, with an estimated 906,000 new cases per year. Universal risk factors include chronic hepatitis B virus (HBV) infection, which contributes substantially to the global HCC burden, especially in endemic settings such as East Asia and sub-Saharan Africa (1-3).

Chronic HBV infection drives hepatocarcinogenesis via multifaceted mechanisms including ongoing inflammation, hepatocyte turnover, fibrosis, integration of viral DNA into the host genome, and eventual clonal expansion of transformed hepatocytes (2,4,5). Because HBV can integrate even in the absence of high-level replication, preventing initial infection is arguably the most effective strategy to block this cascade at its outset (1,2,5).

The advent of HBV vaccination in the 1980s marked a paradigmatic shift in liver disease prevention. The hepatitis B vaccine is widely recognized as the first vaccine with documented anticancer impact, given its success in preventing chronic HBV infection and, by extension, reducing HCC risk (1,2,6). Over four decades of implementation, global coverage of the three-dose HBV vaccination series has expanded into national immunization schedules of more than 190 countries (1,6). In many settings, inclusion of a timely birth dose has helped block mother-to-child transmission, a major route of HBV acquisition in high-prevalence areas (1,6).

Empirical observational and ecological studies have documented declines in HBsAg prevalence, chronic HBV carriage, cirrhosis, and HCC incidence following vaccine introduction. For example, universal childhood vaccination in Taiwan led to >90% reductions in HBsAg prevalence among vaccinated cohorts and progressively lower rates of childhood HCC over time (1,2,5). In Shanghai, joint-point regression analyses revealed accelerating decreases in HCC, particularly among younger male cohorts following implementation of universal HBV immunization (7). Nonetheless, interpretations of those trends may be complicated by secular changes in diagnostics, exposure to other risk factors (e.g., aflatoxin, alcohol, metabolic disease), and varying lag times between infection and cancer onset.

Despite the weight of these findings, prior evidence summaries on this topic have largely been narrative or descriptive in nature (1,2,6,8), with a paucity of formal quantitative syntheses pooling adjusted estimates of HCC across diverse populations. critical questions remain unresolved. First, no prior synthesis has robustly quantified incidence rate ratios (IRRs) or adjusted relative risks (aRRs) linking vaccination status to HCC across varied populations and vaccine formulations. Second, the durability and magnitude of protection—especially into adolescence and early adulthood—are still incompletely characterized. Third, differences by sex, vaccine type (plasma-derived vs. recombinant), and incomplete dosing regimens remain poorly understood at the level of cancer endpoints. Lastly, because many earlier studies report only ecological trends or unadjusted incidence declines, there is a need for rigorous meta-analysis combining both incidence-based and adjusted comparative data to strengthen causal inference.

To address these gaps, we conducted a systematic review and meta-analysis to estimate the pooled effect of HBV vaccination on incident HCC across global settings, synthesizing both occurrence-based IRRs and multivariable-adjusted risks. We performed subgroup analyses by sex, geographical region, vaccine formulation, and dosing regimen to explore heterogeneity and identify factors modifying vaccine effectiveness. Through this work, we aim to provide the most comprehensive quantitative estimate to date of how HBV vaccination contributes to reducing HCC incidence, thereby reinforcing the evidence base for vaccination as an oncologic prevention tool. We present this article in accordance with the PRISMA reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0202/rc) (9).

Methods

Study design and registration

This study was conducted as a systematic review and meta-analysis. The methodology followed a pre-defined protocol developed before data collection, and the final protocol was registered on PROSPERO (ID: 1355073). The research question was framed using the Population-Exposure-Outcome framework (10): among populations with exposure to the HBV vaccine, what is the risk of developing HCC compared with those who were unvaccinated or inadequately vaccinated?

Eligibility criteria

Studies were eligible for inclusion if they met the following criteria: (I) participants had received any formulation of the HBV vaccine (plasma-derived or recombinant), either as part of a national immunization program or within a clinical or observational setting; (II) the study reported HCC as an outcome, expressed in terms of incidence rate, prevalence rate, or RR metrics (e.g., risk ratio, odds ratio, IRR, or hazard ratio); (III) the number of HCC cases exceeded 20 (this threshold was adopted to ensure sufficient event counts for stable effect estimates and reliable variance calculation, given that HCC is a rare outcome and very small event counts produce unstable risk estimates and inflated standard errors when pooled); and (IV) the design was observational (cohort, case-control, or single-arm population study) or randomized controlled trial with extractable comparative or single-arm data. Studies reporting only mortality outcomes, reviews, editorials, conference abstracts, and non-English publications were excluded. When multiple reports described overlapping cohorts, the study with the most comprehensive or updated data was retained.

Search strategy

A comprehensive search of the electronic databases PubMed, Scopus, and Web of Science was conducted on July 24, 2025. The search was designed to identify all relevant studies evaluating the relationship between HBV vaccination and HCC incidence. The PubMed search strategy was developed using a combination of Medical Subject Headings (MeSH) and free-text terms related to “hepatitis B vaccine”, “hepatocellular carcinoma”, and risk metrics, and was adapted for use in the other databases. The full search syntax can be found in Table S1. All references were then imported into EndNote X8 (Clarivate Analytics) for duplicate removal and management.

Study selection

After removal of duplicate records, two reviewers independently screened all remaining titles and abstracts for relevance. Full-text articles of potentially eligible studies were then retrieved and assessed against the inclusion and exclusion criteria. Discrepancies were resolved by consensus or consultation with the senior reviewer.

Data extraction

Two investigators independently extracted data from each included study using a standardized data collection form. Extracted variables included first author, publication year, study design, country/region, study period, total sample size, number of vaccinated and unvaccinated participants, age range, sex distribution, diagnostic criteria for HCC, vaccine formulation, number of doses, and follow-up duration. Where reported, both unadjusted and age- and gender-adjusted effect estimates (IRRs, risk ratios, or hazard ratios) with corresponding 95% confidence intervals (CIs) were extracted. For studies reporting only incidence rates and person-years, IRRs and their standard errors were calculated using standard Poisson-based formula (11). When overlapping or repeated cohorts were identified, the most recent or complete dataset was prioritized.

Quality assessment

Methodological quality was evaluated using the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies (12). Each study was assessed across 14 domains, including population definition, exposure measurement, confounding control, and outcome ascertainment. Each item was scored 0 (no), 1 (cannot determine/not reported/not applicable), or 2 (yes), giving a maximum possible total of 28. Scores ≥21 were considered good quality, 14–20 fair quality, and <14 poor quality. As for randomized trials, the revised Cochrane risk of bias (Rob-2) tool was used. Disagreements were resolved through consensus.

Statistical analysis

All quantitative analyses were performed using Stata version 18.0 (StataCorp, College Station, TX, USA), with confirmatory re-analysis of the adjusted pooled estimates performed in R (version 4.3.2; meta package) to verify the symmetry of 95% CIs on the natural log scale. For each study, log-transformed IRRs or RRs and their corresponding standard errors were derived from the reported estimates or calculated from event counts and person-years. Unadjusted IRRs and aRRs were analyzed in two separate, parallel meta-analyses rather than synthesized together. No hazard ratios or odds ratios were extracted or pooled. This separation preserves the conceptual distinction between incidence-rate comparisons (which inherently account for person-time) and adjusted risk-based comparisons, and avoids any implicit assumption of equivalence between effect-measure types. Pooled estimates were generated using the DerSimonian-Laird random-effects model, which remains the most widely applied estimator in meta-analyses and is the default in standard meta-analytic software; consistency with restricted maximum likelihood (REML) estimation was confirmed during R-based re-analysis (13), which account for between-study heterogeneity. Heterogeneity was quantified using the I² statistic, with values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively.

Subgroup analyses were conducted by country/region, sex, age group, vaccine type (plasma-derived versus recombinant), and number of doses (two versus three or more). When available, multivariable-adjusted estimates (aRRs) were synthesized separately from unadjusted rate ratios to evaluate robustness against confounding. Publication bias was assessed visually through funnel plots and, when ≥10 studies were available, quantitatively using Egger’s regression test. All statistical tests were two-sided, with P values <0.05 considered statistically significant.

Results

Study selection

A total of 1,365 records were retrieved through PubMed, Scopus, and Web of Science searches. After removal of 492 duplicates in EndNote, 873 unique records were screened by title and abstract. Of these, 791 were excluded for irrelevance. Full texts of 82 articles were sought for retrieval; 79 were successfully obtained and assessed. Ultimately, 16 studies met the eligibility criteria and were included in the quantitative synthesis (Figure 1) (7,14-28). Excluded reports primarily focused on HCC-related mortality rather than incidence (n=2), lacked raw or extractable data (n=1), examined non-relevant populations (n=32; comprising studies in patients with established chronic HBV infection or pre-existing cirrhosis evaluating treatment outcomes, hepatitis B immunoglobulin recipients without active vaccination, occupational sub-cohorts unrepresentative of the general population, and animal or in vitro studies), did not include HBV vaccination data (n=14), had no reportable outcomes (n=5), used ineligible study designs (n=8), or were non-English (n=1).

Figure 1 PRISMA 2020 flow diagram of study selection. HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

Study characteristics

Key characteristics of the included studies are summarized in Table 1. The 16 studies were published between 1997 and 2022 and collectively encompassed more than 5 million participants across following countries/regions: Taiwan (n=8), mainland of China (n=5), South Korea (n=1), The Gambia (n=1), and the United States (n=1); the U.S. study comprised an Alaska Native cohort with a high baseline prevalence of HBV genotype F, a unique subset not representative of the broader U.S. population. Most investigations were retrospective cohort studies (n=12), accompanied by two prospective cohorts and two randomized controlled trials. Observation periods spanned 1979 to 2018, covering populations born before and after the introduction of national HBV vaccination programs.

The mean age at follow-up ranged from childhood to early adulthood, with male representation varying between 31.8% and 86.6%. HCC diagnosis methods included capture-recapture algorithms, α-fetoprotein screening combined with imaging, and registry-based ascertainment using AJCC, BCLC, or ICD coding systems. Both plasma-derived and recombinant yeast-derived vaccines were represented, typically administered as three-dose primary series.

Methodological quality

Quality appraisal using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies indicated generally robust study conduct (Table 2). Five studies (35.7%) were rated good quality, and nine (64.3%) were fair quality. Strengths included clearly defined objectives, standardized exposure/outcome measurement, and complete follow-up in registry-based cohorts. Common limitations involved incomplete control of residual confounding, absence of assessor blinding, and limited reporting of potential effect modifiers. No study was rated as poor quality. As for the two included randomized trials, one had some concerns (14) and the other had high risk of bias (26).

Pooled effect of HBV vaccination on HCC incidence

Seven studies provided sufficient raw data to estimate IRRs between vaccinated and unvaccinated populations. The pooled analysis demonstrated a 65% reduction in HCC incidence among vaccinated individuals (IRR =0.35, 95% CI: 0.26–0.47; I²=76.5%), consistent with substantial between-study heterogeneity (Figure 2).

Figure 2 Pooled IRRs of hepatocellular carcinoma among vaccinated vs. unvaccinated populations. CI, confidence interval; IRRs, incidence rate ratios; N/A, not applicable.

By country/region

When stratified by country/region, a consistent protective effect was observed across all settings. The reduction in HCC incidence was most pronounced in mainland of China (IRR =0.15, 95% CI: 0.03–0.66) and Taiwan (IRR =0.34, 95% CI: 0.24–0.46), while the single study from South Korea showed a nonsignificant association (IRR =0.59, 95% CI: 0.32–1.09).

By gender

Both sexes benefited from vaccination, though the magnitude of risk reduction differed. Among males, the pooled IRR was 0.25 (95% CI: 0.12–0.53; I²=94.9%), compared with 0.43 (95% CI: 0.20–0.94; I²=87.2%) among females, indicating a stronger relative effect in males.

By age group

Stratification by age at diagnosis revealed a clear, consistent protective trend across all age categories. The pooled IRR ranged from 0.28 (95% CI: 0.21–0.38) for ages 6–9 years to 0.42 (95% CI: 0.32–0.56) for ages 20–26 years, with negligible heterogeneity (I²=0%).

By combined age-gender subgroups

The combined age-gender analysis demonstrated sustained vaccine effectiveness across strata. Among males, IRRs ranged from 0.26 (95% CI: 0.19–0.37) in those aged 6–9 years to 0.46 (95% CI: 0.04–0.83) in those aged 20–26 years. Corresponding estimates for females were 0.39 (95% CI: 0.19–0.78), 0.38 (95% CI: 0.24–0.58), and 0.39 (95% CI: 0.23–0.68) across the same age strata, all indicating a substantial and consistent reduction in HCC risk. Heterogeneity within these subgroups was minimal (I²=0%), supporting the robustness of these associations.

Adjusted analyses

Twelve studies reported adjusted effect estimates accounting for major covariates such as sex, age, birth cohort, and socioeconomic or clinical factors. The pooled aRR of HCC among vaccinated individuals was 0.33 (95% CI: 0.24–0.46; I²=83.4%), indicating a 67% lower adjusted risk of HCC compared with non-vaccinated counterparts (Figure 3). The leave-one-out sensitivity analysis showed no change in the reported estimate (Figure S1). The funnel plot showed symmetry (Figure S2) and Egger’s regression test did not indicate statistically significant funnel-plot asymmetry (P=0.6879); however, this test is known to have limited statistical power when fewer than 10–15 studies are available, and its result should therefore be interpreted with caution.

Figure 3 Pooled aRRs of hepatocellular carcinoma by subgroup. aRRs, adjusted relative risks; CI, confidence interval; N/A, not applicable.

By country

Subgroup analyses demonstrated consistent vaccine-associated reductions in HCC risk across regions. The strongest association was observed in mainland of China (aRR =0.20, 95% CI: 0.15–0.27; I²=0%), followed by Taiwan (aRR =0.36, 95% CI: 0.24–0.54; I²=87.8%) and South Korea (aRR =0.58, 95% CI: 0.31–1.09). The single study from the United States reported an extremely low aRR (0.01, 95% CI: 0.00–0.61), although the wide CI reflects the rarity of HCC events in that cohort and the small sample size.

By vaccine type

Plasma-derived vaccines were associated with a significantly reduced HCC risk (aRR =0.34, 95% CI: 0.25–0.47; I²=0%). The pooled estimate for recombinant vaccines was directionally consistent with a protective effect but did not reach statistical significance (aRR =0.16, 95% CI: 0.01–3.72; I²=76.0%), with the wide CI reflecting the limited number of contributing studies (n=2) and substantial between-study heterogeneity. Direct head-to-head comparison between vaccine types was therefore not possible.

By vaccine dose

Analyses stratified by vaccine completion status indicated that both two-dose and three-dose regimens substantially reduced HCC risk. The pooled aRRs were 0.23 (95% CI: 0.07–0.39; I²=21%) for individuals who received at least two doses and 0.28 (95% CI: 0.18–0.38; I²=46%) for those who completed three doses.

Discussion

In this systematic review and meta-analysis spanning >5 million individuals across multiple regions, HBV vaccination was associated with a large and durable reduction in incident HCC. The pooled unadjusted effect showed ~65% lower HCC incidence among vaccinated versus unvaccinated populations, and multivariable models confirmed an ~70% risk reduction after adjustment for confounders. These magnitudes are consistent with, and extend, seminal population studies that first demonstrated cancer prevention at scale through HBV immunization. In Taiwan, the introduction of universal infant vaccination in 1984 was followed by a pronounced decline in childhood HCC, providing early quasi-experimental evidence that interrupting HBV transmission translates into fewer cancers. Subsequent follow-up into adolescence and young adulthood showed that benefits persisted as vaccinated birth cohorts aged, reinforcing a causal link between vaccination and reduced carcinogenesis (15,19).

Our findings align with broader global syntheses documenting that universal HBV vaccination programs reduce HBsAg seroprevalence in children, curtail chronic HBV infection, and ultimately lower HCC burden. A recent narrative and data-driven review concluded that the scale-up of HepB3 has driven substantial declines in chronic infection and HCC across regions, with the strongest effects in highly endemic settings. Modelling from the Global Burden of Disease liver collaboration similarly suggests that the counterfactual prevalence of HBsAg would have been markedly higher in 2019 in the absence of vaccination, implying averted downstream cirrhosis and HCC over the life course (1,29).

Evidence from non-Asian settings corroborates generalizability. Among Alaska Natives, combined strategies—universal newborn vaccination, immunization of susceptibles, and surveillance—virtually eliminated symptomatic HBV and HCC in children, underscoring the impact of high coverage and programmatic completeness in a distinct genotype and epidemiologic context. Earlier program reports and subsequent updates from this population are concordant with our pooled effect sizes and support real-world effectiveness beyond East Asia (25,30).

Biological plausibility is strong. Chronic HBV drives HCC through persistent inflammation, integration of HBV DNA into the host genome, and resultant clonal expansion; preventing initial infection interrupts this cascade. Long-term cohort studies indicate that even when anti-HBs titers wane, immune memory persists and anamnestic responses are rapid upon antigenic challenge—helping to explain durable protection we and others observe years after primary series completion. Contemporary reviews of vaccine immunology concur that sustained memory underlies long-term effectiveness, mitigating concerns about routine boosting in the general population (6,18,31).

Our subgroup analyses help refine policy-relevant questions. We observed comparable risk reductions with plasma-derived and recombinant vaccines—mirroring programmatic transitions globally without loss of effectiveness. The protective association with ≥2 doses (with further benefit at ≥3 doses) aligns with the immunogenicity profiles of modern schedules, while reaffirming that timely completion—especially the birth dose—remains critical to block perinatal and early horizontal transmission. The World Health Organization and national technical groups continue to emphasize universal birth-dose within 24 hours followed by completion of the primary series to achieve elimination targets; our estimates provide outcome-level justification (HCC prevention) for these coverage priorities (8).

The geography- and sex-stratified patterns we found are also coherent with known epidemiology. Larger relative effects in mainland of China and Taiwan likely reflect higher baseline HBV prevalence and a greater proportion of HCC attributable to HBV, amplifying the observable benefit of vaccination. Sex differences—with somewhat stronger relative protection among males—are plausible given men’s higher baseline HCC risk from combined viral and non-viral cofactors; vaccination may therefore yield a larger RR reduction against the HBV-attributable component. These interpretations are consistent with regional time-trend analyses showing accelerated post-program declines among younger male cohorts and with population reviews documenting the largest absolute HCC reductions where HBV is the dominant driver (1,32).

Our study has important strengths. We synthesized both rate-based (person-time) and adjusted comparative estimates, demonstrating consistency across statistical frameworks and mitigating concerns that our results simply reflect differential follow-up or crude confounding. Inclusion of large registry-linked cohorts and randomized or quasi-experimental designs improved external validity and allowed informative subgroup analyses by country/region, sex, age at diagnosis, vaccine formulation, and dose.

Limitations warrant consideration. Most included studies were observational; although we pooled adjusted estimates, residual confounding (e.g., alcohol, metabolic syndrome, aflatoxin exposure, variable surveillance intensity) may remain. Specifically, the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), variable alcohol-use patterns across populations, aflatoxin exposure in endemic regions, and host-viral factors such as HBV genotype—where genotypes C and F are associated with substantially higher HCC risk than genotypes B or D, as shown in the Alaska Native cohort—are likely contributors to residual confounding that could not be fully controlled in the source studies (33,34). Pooled adjusted estimates may therefore over- or under-estimate the true vaccine effect depending on the direction of unmeasured confounding. Between-study heterogeneity was high in some strata, likely reflecting differences in underlying HBV epidemiology, secular trends, diagnostic coding, and time since program rollout. The particularly high I² values observed in the sex-stratified analyses (I²=87.2% for females and 94.9% for males) likely reflect variation in baseline HCC incidence rates between sexes, differing follow-up durations, and population-specific risk profiles. Evidence is still concentrated in East Asia (Taiwan, mainland of China, and South Korea contributing the majority of included studies); more long-term follow-up from Africa, South Asia, and the Americas—where genotype distributions, co-infections (HCV/HDV), and metabolic cofactors differ—is needed to confirm generalizability. Finally, lifetime protection into older adulthood remains incompletely characterized as vaccinated cohorts age; ongoing surveillance will clarify the durability of cancer prevention benefits. These caveats echo those raised by authoritative reviews and global policy assessments and point to clear research priorities (1,8).

The public-health implications are substantial. HBV vaccination is among the most effective cancer-prevention interventions ever implemented. Contemporary guidance from WHO and national advisory bodies prioritizes high coverage of the birth dose and completion of the infant series as essential steps toward the 2030 viral hepatitis elimination targets; our pooled estimates translate these programmatic inputs into downstream cancer outcomes. Strengthening perinatal prevention, ensuring cold-chain reliability, reducing missed opportunities, and integrating vaccination with screening and linkage to care for mothers living with HBV can compound benefits across the life course (1,2,35).

Conclusions

In conclusion, across diverse settings, vaccine platforms, and analytic approaches, HBV vaccination is associated with an approximately three-fold reduction in incident HCC. These findings, taken together with decades of mechanistic and programmatic evidence, support universal HBV immunization—including timely birth dose and series completion—as a cornerstone of global liver-cancer prevention strategies. Continued investment in coverage, equity, and long-term cohort surveillance will be pivotal to sustain and extend these gains.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0202/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0202/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0202/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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