HBV breakthrough infection in individuals born to mothers with HBV infection: a systematic review and meta-analysis

BACKGROUND: Despite effective immunoprophylaxis, hepatitis B vaccine breakthrough infection (VBI) can still occur among individuals born to mothers with HBV infection. This study synthesized evidence on the incidence of post-vaccination HBV infection in this high-risk population. METHODS: A systematic literature search was conducted in PubMed, Embase, Scopus, China National Knowledge Infrastructure and Wanfang Chinese databases for articles evaluating VBI in individuals born to mothers with HBV infection. The VBI was characterized by seroconversion to HBsAg and/or anti-HBc positivity at or after 2 years of age, following initial post-immunoprophylaxis HBsAg negativity. The incidence of VBI was pooled after quality assessment. The review followed PRISMA 2020 guidelines and was registered in PROSPERO (CRD420251058273). RESULTS: Among 40 included studies, 37 provided HBsAg data (4,776 individuals; 24,434 person-years) and 29 reported anti-HBc (6,190 individuals; 16,663 person-years). The pooled cumulative incidence of HBsAg positivity was 0.24% (95% CI: 0.01-0.66%) and the incidence rate was 2.19 per 1,000 person-years (95% CI: 1.01-4.74). Anti-HBc positivity was higher, with a pooled cumulative positivity of 4.57% (95% CI: 2.18-7.66%) and an incidence rate of 19.69 (95% CI: 6.05-64.01) per 1,000 person-years. Subgroup analyses showed comparable HBsAg positivity between children born to mothers who were HBeAg-positive and HBeAg-negative (0.38% vs. 0.34%), while anti-HBc positivity differed markedly (6.81% vs. 0.64%). Consistently lower infection rates were observed among children who received booster immunization (HBsAg: 0.00% vs. 0.34%; anti-HBc: 0.37% vs. 3.88%), higher vaccine doses (10 µg vs. 5 µg: HBsAg 0.32% vs. 0.84%; anti-HBc 3.84% vs. 11.12%), or yeast-derived recombinant vaccines (HBsAg: 0.16% vs. 0.95%; anti-HBc: 4.50% vs. 7.95%), whereas anti-HBc positivity was higher among children older than 5 years than among those aged ≤ 5 years (9.61% vs. 2.38%). CONCLUSIONS: HBsAg positivity after successful neonatal immunoprophylaxis was rare, but the higher anti-HBc positivity suggests cumulative HBV exposure in this population, particularly among children born to HBeAg-positive mothers. Sustaining long-term protection through optimized vaccine strategies, such as timely boosters or higher postnatal dose regimens, may further reduce VBI risk in high-risk population and warrants further evaluation.