Vaccine 33 (2015) 15–16
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Letter to the Editor Hepatitis B vaccine response among infants born to hepatitis B surface antigen-positive women Sir, The study of Ko et al. [1] showed that 5.3% of uninfected infants did not respond to a primary 3- or 4-dose hepatitis B vaccine series, and that the incidence of vaccine non-response was inversely correlated with the interval of post-vaccination serological testing (PVST), being 2.0% at 1–2 months and 21.6% at 15–16 months. It has been reported before that antibody positive rate declined from 100% at age 2 years to 75% at age 6 years for complete vaccinees [2], and that the incidence of undetected antibody levels was 36.1%, 20% and 14.6% for the 5–8 years, 2.5–5 years, and 1–2.5 years groups respectively [3]. Indeed, anamnestic responses to booster vaccination at 15 years of age could not be found in half of the children vaccinated at birth [4]. Whether those apparent vaccine non-responders diagnosed in childhood retained an anamnestic response remains unclear, as despite immunization, 1.3–3.5% of the infants became HBsAg carriers 15 years later [5], and in another study 1.3% of complete vaccinees were HBsAg positive at age 2–6 years [2]. In Micronesians vaccinated at birth, 8% had evidence of past HBV infection 15 years later while only 7.3% of uninfected individuals had positive antibody, and an anamnestic response could be found in 47.9% in the remaining individuals [6]. It is likely that vaccine non-response actually represents genuine vaccine failure in some cases, as we have found that among first-year university students in Hong Kong, there was a marked and significant increase in HBsAg carriage from 0.9% in those aged ≤18 years to 9.8% in those aged ≥21 years among subjects born in 1983–1988 after the introduction of selective HBV vaccination [7]. Similarly among teenage mothers, the prevalence increased significantly from 1.2% in those aged ≤16 years to 8.3% in those aged 19 years among subjects born after the introduction of selective vaccination [8]. Taken together, the epidemiological evidence suggested that the primary 3-dose hepatitis B vaccine series, as given in Hong Kong, does not ensure life-long protection in all vaccinees. In Hong Kong, the Government Health policy dictates that infants born to HBsAg positive mothers receive immunoglobulin and the first dose of HBV vaccine after birth, either in the Delivery Suite or shortly after admission into the postnatal nursery, thus within 12 h of birth, except for very sick or premature babies. The second and third doses are given at the age of one and six months respectively [9], but neither PVST nor booster with one or more doses at an older age is required. To address our concern that a primary series may not be sufficient to confer prolonged protection [7,8], we have initiated an on-going prospective survey on vaccine response in local Chinese children born in our hospital to HBsAg positive mothers since August 2010, and examined their anti-HBs status at the age of 18–24 months to determine the incidence of and factors associated with vaccine non-response. We chose the age of http://dx.doi.org/10.1016/j.vaccine.2014.05.036 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
Table 1 Maternal and fetal characteristics and HBV vaccine response in 160 Chinese children born to HBsAg positive mothers. Results expressed in mean ± SD or number (%) as indicated. Maternal age (years) Maternal HBeAg positive status (%) Nulliparas (%) Baby birth weight (g) Number (%) 500 IU/mL (%) HBsAg detected (%) a
32.0 ± 4.5 43 (26.9%) 70 (43.8%) 3161 ± 417 10 (6.3%) 39.1 ± 1.6 10 (6.3%) 76 (47.5%) 13.0 ± 1.7 77 (48.1%) 1.60 ± 0.13 36 (22.5%) 39 (24.4%) 53 (33.1%) 32 (20.0%) 1 (0.6%)
Including the HBsAg positive child.
18–24 months for our study because of a recent Press Statement issued by the Department of Health of the Hong Kong Government that the percentage of children aged 2 to 5 years who had completed the three doses of hepatitis B vaccines exceeded 99.5%, and that the HBsAg seroprevalence was 0.78%. Thus the likelihood of any of our study subjects not having completed the vaccination program would have been minimal. Preliminary analysis of the 160 children who have completed the assessment indicated that only one (0.6%) child was positive for HBsAg while 22.0% (35/159) of the non-infected children were non-responders (Table 1), a finding that is strikingly similar to, and in support of, that of Ko et al. [1], with the exception that no correlation between the anti-HBs level in the children with PVST interval in months (Spearman’s rho = 0.043, p = 0.632), or between the category of anti-HBs (100 to 500, and >500 IU/mL) with the category of interval in months (≤3, 3–6, 6.1–12, 12.1–18, >18 months) (Spearman’s rho 0.061, p = 0.447), was found. It is possible that our much smaller sample size of 160 lacked the power to demonstrate such a correlation compared with the 8654 mothers/pregnancies in the aforementioned study [1], but we cannot discount the effect of other factors that could have impacted on vaccine response, and which are being analyzed. Thus regardless of the location and ethnic background, approximately one in five of the uninfected children born to HBsAg carrier mothers with PVST performed at age 15–16 months in the US and 18–24 months in Hong Kong, demonstrated non-response to a 3–4 dose primary series of hepatitis B vaccine. Unless there is timely PVST, and a mandatory second series for non-responders with timely PVST as described by Ko et al., the undiagnosed nonresponders could grow up unprotected so that when they come
16
Letter to the Editor / Vaccine 33 (2015) 15–16
of age, they could be infected through horizontal transmission, and which would have explained our observed dramatic increase in the age-specific prevalence of hepatitis B infection in university students [7] and teenage mothers [8]. In view of the findings of Ko et al. [1] and our preliminary observations, further studies are warranted to determine which of the following approach, i.e. increasing the primary series to four doses; introducing mandatory PVST with a second series for non-responders; or providing a mandatory booster dose or second series during adolescence; would be most cost-effective in ensuring the protection of the offspring of HBV-infected mothers in high endemicity populations like the Chinese. 1. Conflict of interest None of the authors have any conflict of interest regarding the study or the manuscript. References [1] Ko SC, Schillie SF, Walker T, Veselsky SL, Nelson N, Lazaroff J, et al. Hepatitis B vaccine response among infants born to hepatitis B surface antigen-positive women. Vaccine 2014, http://dx.doi.org/10.1016/j.vaccine.2014.01.099. [2] Lin D-B, Wang H-M, Lee Y-L, Ling U-P, Changlai S-P, Chen C-J. Immune status in preschool children born after mass hepatitis B vaccination program in Taiwan. Vaccine 1998;16:1683–7. [3] Gold Y, Somech R, Mandel D, Peled Y, Reif S. Decreased immune response to hepatitis B eight years after routine vaccination in Israel. Acta Paediatr 2003;92:1158–62. [4] Hammitt LL, Hennessy TW, Fiore AE, Zanis C, Hummel KB, Dunaway E, et al. Hepatitis B immunity in children vaccinated with recombinant hepatitis B vaccine beginning at birth: a follow-up study at 15 years. Vaccine 2007;25:6958–64. [5] Lu C-Y, Chiang B-L, Chi W-K, Chang M-H, Ni Y-H, Hsu H-M, et al. Waning immunity to plasma-derived hepatitis B vaccine and the need for boosters 15 years after neonatal vaccination. Hepatology 2004;40:1415–20.
[6] Bialek SR, Bower WA, Novak R, Helgenberger L, Auerbach SB, Williams IT, et al. Persistence of protection against hepatitis B virus infection among adolescents vaccinated with recombinant hepatitis B vaccine beginning at birth. A 15-year follow-up study. Pediatr Infect Dis J 2008;27:881–5. [7] Suen SSH, Lao TT, Chan OK, Lau TK, Leung TY, Chan PKS. Relationship between age and prevalence of hepatitis B infection in first-year university students in Hong Kong. Infection 2013;41:529–35. [8] Lao TT, Sahota DS, Suen SSH, Chan PKS, Leung TY. Impact of neonatal hepatitis B vaccination programme on age-specific prevalence of hepatitis B infection in teenage mothers in Hong Kong. Epidemiol Infect 2013, http://dx.doi.org/10.1017/S0950268812002701. [9] Department of Health. Hong Kong Surveillance of viral hepatitis in Hong Kong; 2006 [update report] http://www.info.gov.hk/hepatitis/doc/hepsurv06.pdf
Terence T. Lao ∗ Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong K.L. Cheung Department of Paediatrics & Adolescent Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Vincent Wong Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong ∗ Corresponding
author. Tel.: +852 2632 1290; fax: +852 2636 0008. E-mail address: [email protected] (T.T. Lao) 10 March 2014 Available online 8 July 2014
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Letter to the Editor Hepatitis B vaccine response among infants born to hepatitis B surface antigen-positive women Sir, The study of Ko et al. [1] showed that 5.3% of uninfected infants did not respond to a primary 3- or 4-dose hepatitis B vaccine series, and that the incidence of vaccine non-response was inversely correlated with the interval of post-vaccination serological testing (PVST), being 2.0% at 1–2 months and 21.6% at 15–16 months. It has been reported before that antibody positive rate declined from 100% at age 2 years to 75% at age 6 years for complete vaccinees [2], and that the incidence of undetected antibody levels was 36.1%, 20% and 14.6% for the 5–8 years, 2.5–5 years, and 1–2.5 years groups respectively [3]. Indeed, anamnestic responses to booster vaccination at 15 years of age could not be found in half of the children vaccinated at birth [4]. Whether those apparent vaccine non-responders diagnosed in childhood retained an anamnestic response remains unclear, as despite immunization, 1.3–3.5% of the infants became HBsAg carriers 15 years later [5], and in another study 1.3% of complete vaccinees were HBsAg positive at age 2–6 years [2]. In Micronesians vaccinated at birth, 8% had evidence of past HBV infection 15 years later while only 7.3% of uninfected individuals had positive antibody, and an anamnestic response could be found in 47.9% in the remaining individuals [6]. It is likely that vaccine non-response actually represents genuine vaccine failure in some cases, as we have found that among first-year university students in Hong Kong, there was a marked and significant increase in HBsAg carriage from 0.9% in those aged ≤18 years to 9.8% in those aged ≥21 years among subjects born in 1983–1988 after the introduction of selective HBV vaccination [7]. Similarly among teenage mothers, the prevalence increased significantly from 1.2% in those aged ≤16 years to 8.3% in those aged 19 years among subjects born after the introduction of selective vaccination [8]. Taken together, the epidemiological evidence suggested that the primary 3-dose hepatitis B vaccine series, as given in Hong Kong, does not ensure life-long protection in all vaccinees. In Hong Kong, the Government Health policy dictates that infants born to HBsAg positive mothers receive immunoglobulin and the first dose of HBV vaccine after birth, either in the Delivery Suite or shortly after admission into the postnatal nursery, thus within 12 h of birth, except for very sick or premature babies. The second and third doses are given at the age of one and six months respectively [9], but neither PVST nor booster with one or more doses at an older age is required. To address our concern that a primary series may not be sufficient to confer prolonged protection [7,8], we have initiated an on-going prospective survey on vaccine response in local Chinese children born in our hospital to HBsAg positive mothers since August 2010, and examined their anti-HBs status at the age of 18–24 months to determine the incidence of and factors associated with vaccine non-response. We chose the age of http://dx.doi.org/10.1016/j.vaccine.2014.05.036 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
Table 1 Maternal and fetal characteristics and HBV vaccine response in 160 Chinese children born to HBsAg positive mothers. Results expressed in mean ± SD or number (%) as indicated. Maternal age (years) Maternal HBeAg positive status (%) Nulliparas (%) Baby birth weight (g) Number (%) 500 IU/mL (%) HBsAg detected (%) a
32.0 ± 4.5 43 (26.9%) 70 (43.8%) 3161 ± 417 10 (6.3%) 39.1 ± 1.6 10 (6.3%) 76 (47.5%) 13.0 ± 1.7 77 (48.1%) 1.60 ± 0.13 36 (22.5%) 39 (24.4%) 53 (33.1%) 32 (20.0%) 1 (0.6%)
Including the HBsAg positive child.
18–24 months for our study because of a recent Press Statement issued by the Department of Health of the Hong Kong Government that the percentage of children aged 2 to 5 years who had completed the three doses of hepatitis B vaccines exceeded 99.5%, and that the HBsAg seroprevalence was 0.78%. Thus the likelihood of any of our study subjects not having completed the vaccination program would have been minimal. Preliminary analysis of the 160 children who have completed the assessment indicated that only one (0.6%) child was positive for HBsAg while 22.0% (35/159) of the non-infected children were non-responders (Table 1), a finding that is strikingly similar to, and in support of, that of Ko et al. [1], with the exception that no correlation between the anti-HBs level in the children with PVST interval in months (Spearman’s rho = 0.043, p = 0.632), or between the category of anti-HBs (100 to 500, and >500 IU/mL) with the category of interval in months (≤3, 3–6, 6.1–12, 12.1–18, >18 months) (Spearman’s rho 0.061, p = 0.447), was found. It is possible that our much smaller sample size of 160 lacked the power to demonstrate such a correlation compared with the 8654 mothers/pregnancies in the aforementioned study [1], but we cannot discount the effect of other factors that could have impacted on vaccine response, and which are being analyzed. Thus regardless of the location and ethnic background, approximately one in five of the uninfected children born to HBsAg carrier mothers with PVST performed at age 15–16 months in the US and 18–24 months in Hong Kong, demonstrated non-response to a 3–4 dose primary series of hepatitis B vaccine. Unless there is timely PVST, and a mandatory second series for non-responders with timely PVST as described by Ko et al., the undiagnosed nonresponders could grow up unprotected so that when they come
16
Letter to the Editor / Vaccine 33 (2015) 15–16
of age, they could be infected through horizontal transmission, and which would have explained our observed dramatic increase in the age-specific prevalence of hepatitis B infection in university students [7] and teenage mothers [8]. In view of the findings of Ko et al. [1] and our preliminary observations, further studies are warranted to determine which of the following approach, i.e. increasing the primary series to four doses; introducing mandatory PVST with a second series for non-responders; or providing a mandatory booster dose or second series during adolescence; would be most cost-effective in ensuring the protection of the offspring of HBV-infected mothers in high endemicity populations like the Chinese. 1. Conflict of interest None of the authors have any conflict of interest regarding the study or the manuscript. References [1] Ko SC, Schillie SF, Walker T, Veselsky SL, Nelson N, Lazaroff J, et al. Hepatitis B vaccine response among infants born to hepatitis B surface antigen-positive women. Vaccine 2014, http://dx.doi.org/10.1016/j.vaccine.2014.01.099. [2] Lin D-B, Wang H-M, Lee Y-L, Ling U-P, Changlai S-P, Chen C-J. Immune status in preschool children born after mass hepatitis B vaccination program in Taiwan. Vaccine 1998;16:1683–7. [3] Gold Y, Somech R, Mandel D, Peled Y, Reif S. Decreased immune response to hepatitis B eight years after routine vaccination in Israel. Acta Paediatr 2003;92:1158–62. [4] Hammitt LL, Hennessy TW, Fiore AE, Zanis C, Hummel KB, Dunaway E, et al. Hepatitis B immunity in children vaccinated with recombinant hepatitis B vaccine beginning at birth: a follow-up study at 15 years. Vaccine 2007;25:6958–64. [5] Lu C-Y, Chiang B-L, Chi W-K, Chang M-H, Ni Y-H, Hsu H-M, et al. Waning immunity to plasma-derived hepatitis B vaccine and the need for boosters 15 years after neonatal vaccination. Hepatology 2004;40:1415–20.
[6] Bialek SR, Bower WA, Novak R, Helgenberger L, Auerbach SB, Williams IT, et al. Persistence of protection against hepatitis B virus infection among adolescents vaccinated with recombinant hepatitis B vaccine beginning at birth. A 15-year follow-up study. Pediatr Infect Dis J 2008;27:881–5. [7] Suen SSH, Lao TT, Chan OK, Lau TK, Leung TY, Chan PKS. Relationship between age and prevalence of hepatitis B infection in first-year university students in Hong Kong. Infection 2013;41:529–35. [8] Lao TT, Sahota DS, Suen SSH, Chan PKS, Leung TY. Impact of neonatal hepatitis B vaccination programme on age-specific prevalence of hepatitis B infection in teenage mothers in Hong Kong. Epidemiol Infect 2013, http://dx.doi.org/10.1017/S0950268812002701. [9] Department of Health. Hong Kong Surveillance of viral hepatitis in Hong Kong; 2006 [update report] http://www.info.gov.hk/hepatitis/doc/hepsurv06.pdf
Terence T. Lao ∗ Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong K.L. Cheung Department of Paediatrics & Adolescent Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Vincent Wong Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong ∗ Corresponding
author. Tel.: +852 2632 1290; fax: +852 2636 0008. E-mail address: [email protected] (T.T. Lao) 10 March 2014 Available online 8 July 2014
