• Tzu-Wei Wu Ph.D.,

    1. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
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  • Hans Hsienhong Lin M.D.,

    1. Department of Gastroenterology, Buddhist Tzu Chi Hospital Taipei Branch, New Taipei City, Taiwan
    2. Department of Internal Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan
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  • Li-Yu Wang Ph.D.

    1. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
    2. Department of Public Health, Taipei Medical University, Taipei City, Taiwan
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  • Potential conflict of interest: Nothing to report.


We would like to thank Romano et al. for their interest in our study. In their Letter to the Editor, they summarized the most important findings of our work and pointed out that immunological memory usually persists in subjects who did not have a protective level of antibody to hepatitis B surface antigen (anti-HBs) titer. However, without protective levels of anti-HBs, memory cells alone are probably unable to protect against acute infection promptly.[1] Furthermore, duration of humoral immunity to viral and vaccine antigens varies significantly.[2] In Rosado et al.'s study, the mean number of anti-HBs immunoglobulin G–secreting cells in children who received hepatitis B vaccination 5 years before and had detectable residual anti-HBs titers was 11.3 cells/106 plated cells.[3] A similar study assayed hepatitis B surface antigen (HBsAg)-specific memory cells in a group of subjects that completed the vaccination program as infants, but who did not retain protective levels of anti-HBs titers at 15-18 years of age.[4] They found that approximately two thirds of these cohort members had HBsAg-specific memory cells <1 cell/106 plated cells before booster. After a booster dose of hepatitis B vaccination, 27.2% still had memory cells <1 cell/106 plated cells.[4] Consequently, it seems that the number of memory cells decreases significantly during the second decade of life. The minimum numbers of memory cells to induce an effective immune response against infection and reactivation, especially in individuals with undetectable residual anti-HBs titers, remains an issue to be investigated.

In their Letter to the Editor, Romano et al. pointed out that booster vaccination may be needed for regions where risks of contracting hepatitis B virus (HBV) infection and becoming chronic are high. Because the cumulative risk of chronic HBV infection in subjects who did not received hepatitis B immune globulin was low, our results did not support boosting the whole neonatally vaccinated cohort.[5] In our study, the cumulative risk of chronic HBV infection in subjects with maternal hepatitis B e antigen (HBeAg) positivity and high HBsAg titers were 17.8% and 11.1%, respectively.[5] Based on the figures in two empirical studies,[6, 7] the estimated cumulative risk of chronic HBV infection in individuals with low maternal HBsAg titers was 4%∼5%. Accordingly, our results indicated that booster vaccination is necessary for children of HBeAg-positive mothers and should be considered for children of HBsAg-positive mothers.

Among children of HBsAg-carrier mothers, average incidence rates of HBV breakthrough infection for 5-10 years of age were similar to[8] or greater than[9] those of 1-5 years of age. The 10-year cumulative risk of HBV breakthrough infection were 11%∼13%. Among 127 antibody to hepatitis B core antigen (anti-HBc)-positive subjects, 4 became chronically infected.[8, 9] These findings supported that, even in high-risk children, the protective effects of hepatitis B vaccination can last for at least 10 years. However, HBV breakthrough infection increased prominently thereafter. Among a cohort of adolescents with maternal HBeAg positivity and who had developed protective levels of anti-HBs during infancy, the anti-HBc-positive rate was 33.3% at 15 years of age.[10] The anti-HBc-positive rates of the first decade in children of HBeAg-positive mothers were 9.5% and 14.3%, respectively, for whom with and without booster vaccination was at 5 years of age.[11] For their second decade of life, these rates were 22.2% and 28.6%, respectively.[11] More important, HBV DNA was detected with a high frequency (81 of 106) in a cohort of HBsAg(−)/anti-HBs(+)/anti-HBc(+) young adults who were vaccinated neonatally.[12]

Based on several lines of evidences, including that (1) risks of breakthrough HBV infections increase prominently after 10 years of age, (2) immunological memory against HBsAg declines significantly during 5-15 years after primary vaccination, (3) occurrence of occult HBV infection is frequently noted in anti-HBc-positive individuals vaccinated neonatally, and (4) moderate-to-high cumulative risk of chronic HBV infections in adolescents who had maternal HBsAg and/or HBeAg positivity, we recommend, in addition to immunocompromised individuals, to boost individuals who had maternal HBsAg and/or HBeAg positivity 10 years after primary vaccination.

  • Tzu-Wei Wu, Ph.D.1

  • Hans Hsienhong Lin, M.D.2,3

  • Li-Yu Wang, Ph.D.1,4

  • 1Department of Medicine Mackay Medical College New Taipei City, Taiwan

  • 2Department of Gastroenterology Buddhist Tzu Chi Hospital Taipei Branch New Taipei City, Taiwan

  • 3Department of Internal Medicine School of Medicine Tzu Chi University Hualien, Taiwan

  • 4Department of Public Health Taipei Medical University Taipei City, Taiwan