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Impact of hepatitis B vaccination among children in Guangdong Province, China
International Journal of Infectious Diseases 16 (2012) e692–e696
Contents lists available at SciVerse ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Impact of hepatitis B vaccination among children in Guangdong Province, China Jianpeng Xiao a,b, Jikai Zhang a, Chenggang Wu a, Xiaoping Shao a, Guowen Peng a, Zhiqiang Peng a, Wenjun Ma a,b, Yonghui Zhang a, Huizhen Zheng a,* a b
Guangdong Provincial Center for Disease Control and Prevention, 176 Xingang Xi Road, Haizhu District, Guangzhou, China 510300 Guangdong Institute of Public Health, Guangzhou, China
A R T I C L E I N F O
S U M M A R Y
Article history: Received 5 January 2012 Accepted 14 May 2012
Objective: To evaluate the impact of the universal infant hepatitis B vaccination program on hepatitis B virus (HBV) infection in Guangdong Province, China. Methods: In 2006, a serosurvey was conducted in Guangdong Province among children aged <15 years, 14 years after the introduction of universal infant hepatitis B vaccination. The participants were selected by stratified, multi-stage random sampling. Demographic characteristics and hepatitis B vaccination history were collected by a questionnaire and a review of the vaccination records, and serum specimens were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis B surface antigen (anti-HBs) by ELISA. The prevalence rate of HBV serological markers and the rate of immunization coverage in this survey were compared with those of the 1992 and 2002 surveys. Results: A total of 1967 children aged <15 years participated in 2006. The prevalence rate of HBsAg decreased from 19.86% in the 1992 survey to 4.91% in the 2006 survey. The rates of three-dose and timely birth dose coverage of hepatitis B vaccine were 92.40% and 70.84%, respectively, among children born during the period 2002–2005. The prevalence of HBsAg was significantly lower among fully immunized children (1.99%) than among unvaccinated children (5.56%). Conclusions: Guangdong Province has successfully integrated the hepatitis B vaccine into routine immunization programs and this has had a very significant impact on decreasing the HBsAg carrier rate among children. ß 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: William Cameron, Ottawa, Canada Keywords: Prevalence Hepatitis B vaccination Vaccination coverage
1. Introduction Hepatitis B virus (HBV) infection is a serious health problem in China.1 In 1992, the national hepatitis serological survey revealed that the prevalence of hepatitis B surface antigen (HBsAg) was 9.75% in the population aged 1–59 years, and the rate in the 1–4 years age group was as high as the overall rate. Among the six regions of China, the south region had the highest HBsAg prevalence rate.2 Perinatal transmission is a major mode of HBV transmission in China.3,4 Therefore, China has made great efforts to establish universal infant immunization. The hepatitis B vaccine (HepB) was recommended for routine immunization of infants by the Ministry of Health in 1992. HepB was then fully integrated into the routine immunization program from 2002, and infants have been vaccinated without any charge since June 1, 2005.5,6
* Corresponding author. Tel.: +86 20 89023840; fax: +86 20 84459326. E-mail address: [email protected] (H. Zheng).
Guangdong Province is located in the south of China and is an area with a developed economy and an open culture. This is a highly populated province – the population was 95 million in 2006. The 1992 serological survey revealed shocking figures for the prevalence of HBsAg in Guangdong; this was as high as 17.85% in the general population, and 19.86% of children aged <15 years were found to carry HBV, making this the first ranking province in China.7 Following this survey, a long-term program to vaccinate newborns against HBV was started in Guangdong; more than 1.5 million newborns benefited from the HepB vaccination program each year. In addition to the national vaccination program, a massive HepB immunization campaign was carried out in Guangdong Province in 2001, in which children aged <18 years with incomplete HepB vaccination were required to obtain catchup injections. In 2002, another hepatitis B serological survey was conducted in Guangdong,8 10 years after the introduction of the universal infant HepB vaccination. Results showed that the HBsAg prevalence rate among children had decreased dramatically, from 19.86% to 8.56%. The latest provincial hepatitis B serological survey was conducted in 2006, 4 years after the routine immunization
1201-9712/$36.00 – see front matter ß 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijid.2012.05.1027
J. Xiao et al. / International Journal of Infectious Diseases 16 (2012) e692–e696
program. This survey aimed to determine the prevalence rates of HBV markers and HepB vaccination coverage among children born after universal hepatitis B vaccination was introduced, and to compare the results with those of the 1992 and 2002 surveys. 2. Materials and methods 2.1. Study population and sample method In September 2006, a cross-sectional serological survey was conducted in Guangdong Province, China. The target population was children aged <15 years at each of six national disease surveillance points (DSP), which were selected by the Chinese Center for Disease Control and Prevention (CDC) to be representative of the population of Guangdong Province. The six DSP could be divided into an urban group (Guangzhou, Shanwei, Yunfu) and a rural group (Shaoguan, Zhaoqing, Meizhou) (Figure 1). The subjects were selected by stratified, multi-stage random sampling in these six DSP. Three sub-districts in each urban district, two towns in each rural county, and one resident commission (village) in each sub-district (town) were selected randomly. In the selected resident commission (village), all children aged 1–4 years were interviewed and participants aged 5–14 years were chosen by systematic sampling. 2.2. Investigation A house-to-house investigation was completed by trained staff using a standard questionnaire. Written informed consent was provided by the parents of all children who participated in this survey. The child’s immunization status was recorded from their home immunization certificate, or if not available, the immunization information was recorded from the parent’s description. Otherwise, the immunization information was recorded as unvaccinated or unknown. Full vaccination was defined as receipt of three doses of HepB within 12 months, as documented by any immunization record. Timely birth-dose coverage was defined as receipt of the first dose of HepB within 24 h after birth.
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2.3. Specimen collection and laboratory testing The laboratory testing method was in accordance with a previous report.5 Blood samples were obtained from each study participant (4 ml for children aged 2 years and 2 ml for children aged <2 years). Serum was initially separated in the local laboratories and was subsequently transported to provincial laboratories. All serum specimens were sent to the National Hepatitis Laboratory for testing. HBsAg, antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc) were detected using an ELISA kit. 2.4. Data analysis All data were double-inputted using Epi Data 3.1 software and were checked for consistency and accuracy. The data were analyzed using SPSS 16.0 software (SPSS, Chicago, IL, USA). The rate was weighted by age, gender, and district on the basis of the data of the 2000 national census of Guangdong Province. 3. Results 3.1. Characteristics of the study population Overall, 1967 children aged <15 years participated in 2006. A total of 763 were aged 1–4 years and 1204 were aged 5–14 years. The sex and district distributions were as follows: 1078 males (54.8%) and 889 females (45.2%); 985 (50.1%) from urban areas and 982 (49.9%) from rural areas. 3.2. Distribution of HBV serological markers by age In the 2006 serological survey, the weighted prevalence rates of HBsAg, anti-HBs, anti-HBc, and HBV infection were 4.91%, 61.87%, 9.35%, and 18.00%, respectively, among children aged <15 years (Table 1). The HBsAg prevalence decreased steadily with decreasing age and the prevalence rate was lowest in 1-year-old children (0.64%) (Figure 2). The anti-HBs prevalence rate in 1-year-olds was
Figure 1. Geographic distribution of districts sampled in Guangdong Province, China.
Total
Rural
significantly higher than that for the other age groups. The highest prevalence rates of anti-HBc and HBV infection were observed in children aged 10–14 years. In comparison with the 1992 and 2002 surveys, which investigated 1032 and 1963 children aged <15 years, respectively, the HBsAg prevalence rate among children decreased dramatically from 19.86% to 4.91%, and the HBV infection rate decreased from 71.41% to 18.00%, while the anti-HBs rate increased from 37.21% to 61.87%. These trends were observed in all age groups (Figure 2). HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBs, antibody to hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core antigen; 95% CI, 95% confidence interval.
17.16 14.81–19.51 18.84 16.30–19.70 18.00 16.30–19.70 17.06 13.66–20.46 35.81 33.38–38.24 31.33 29.28–33.38 55.92 51.05–60.79 77.26 73.99–80.53 71.41 68.65–74.17 65.99 63.03–68.95 57.74 54.65–60.83 61.87 59.72–64.02 1.93 1.07–2.79 7.43 5.79–9.07 4.91 3.96–5.86 Urban/rural Urban
Female
40.11 35.31–44.91 35.01 31.29–38.73 37.21 34.26–40.16 1.97 0.71–3.32 10.91 9.33–12.49 8.56 7.32–9.80 8.55 5.81–11.29 23.4 20.10–26.70 19.86 17.43–22.29
75.41 71.51–79.31 60.83 58.35–63.31 68.01 65.95–70.07
45.05 40.17–49.93 60.01 56.19–63.83 53.59 50.55–56.63
13.22 10.15–16.29 25.50 23.29–27.71 22.57 20.72–24.42
4.57 3.27–5.87 14.15 11.97–16.33 9.35 8.06–10.64
18.46 16.14–20.78 17.44 14.95–19.93 32.32 29.57–35.07 30.07 26.99–33.15 74.64 71.02–78.26 67.65 63.45–71.85 63.27 60.39–66.15 60.18 56.96–63.40 Sex Male
5.19 3.87–6.51 4.05 2.75–6.35
37.59 33.56–41.62 36.76 32.43–41.09 10.05 8.28–11.82 6.60 4.93–8.27 23.56 20.03–27.09 15.55 12.29–18.81
66.12 63.34–68.90 69.95 66.87–73.03
55.58 51.45–59.71 51.26 46.77–55.75
23.16 20.68–25.64 21.82 19.04–24.60
9.37 7.63–11.11 9.34 7.43–11.25
2006 2002 1992 2006 2002
Anti-HBs prevalence,%; 95% CI
1992 2002 1992
2006 HBsAg prevalence,%; 95% CI Group
Table 1 Prevalence rate of HBV markers among children aged 1–14 years in Guangdong Province, in 1992, 2002, and 2006
Anti-HBc prevalence,%; 95% CI
2006
1992
2002
J. Xiao et al. / International Journal of Infectious Diseases 16 (2012) e692–e696
HBV infection prevalence,%; 95% CI
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3.3. Distribution of HBV serological markers by sex and district HBsAg prevalence was significantly higher for males than females (5.19% vs. 4.05%, p < 0.05) and this phenomenon was also observed in both the 1992 and 2002 surveys (Table 1). The HBsAg prevalence among persons living in rural areas was higher than among those living in urban areas (7.43% vs. 1.93%, p < 0.01) and the prevalence of anti-HBs was higher in urban than in rural areas (65.99% vs. 57.74%, p < 0.05). Similarly, these phenomena were also observed in both the 1992 and 2002 surveys (Table 1). 3.4. Immunization coverage of hepatitis B vaccine for children aged <5 years The survey found that immunization records were not well kept during the 1990s; the HepB vaccination history for those with no written records was obtained by interviewing the child’s parents, so the immunization history in a large portion of children aged >10 years was undefined. Thus, the analysis of immunization coverage was based only on children aged <5 years. For children born during the period 2002–2005, the rates of weighted three-dose and timely birth dose coverage of HepB were 92.40% and 70.84%, respectively. The coverage rate increased steadily with decreasing age. In addition, although there was no significant difference in the rates of three-dose coverage between urban and rural areas, the prevalence of timely birth dose coverage was higher in urban than in rural areas (80.51% vs. 58.80%, p < 0.05). Compared to the same age group in the 2002 survey, the rates of three-dose and timely birth dose coverage of HepB increased from 86.10% to 92.40%, and from 65.71% to 70.84%, respectively (Table 2). 3.5. Prevalence of HBsAg and other HBV markers and immunization history Different histories of hepatitis B immunization led to obvious differences in the distributions of HBV prevalence. The prevalence of HBsAg was significantly lower among children who had been fully vaccinated than among unvaccinated children and among those with unknown immunization status. The prevalence of HBsAg was 1.99% among children born during 2002–2005 who received the full three-dose immunization series, while among children who had not been immunized, the prevalence of HBsAg was 5.56%. The prevalence of anti-HBs was higher among fully immunized children (72.65%) than among unvaccinated children (27.78%). The prevalence of anti-HBc was significantly lower among fully immunized children (3.28%) than among unvaccinated children (5.56%). A comparison between the 2002 and 2006 survey results showed that they were in accordance with each other (Table 3). 4. Discussion Endemic HBV infection is a serious health problem in China, especially in Guangdong Province.7 Vaccination is considered the most cost-effective way to control hepatitis B, and immunization
J. Xiao et al. / International Journal of Infectious Diseases 16 (2012) e692–e696
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Figure 2. Comparison of the age-specific prevalence rate of (A) HBsAg, (B) anti-HBs, (C) anti-HBc, and (D) HBV infection among children aged 1–14 years in 1992, 2002, and 2006 in Guangdong Province.
Table 2 Immunization coverage of hepatitis B vaccine for children aged 1–4 years in 2002 and 2006 2006
2002 Age, years
Number investigated
Three dose coverage % (95% CI)
Timely birth dose coverage % (95% CI)
Number investigated
Three dose coverage % (95% CI)
Timely birth dose coverage % (95% CI)
1 2 3 4 Urban/rural Urban Rural Total
131 112 145 137
90.84 86.77 81.38 78.42
77.31 68.69 62.10 54.55
(70.14–84.48) (60.10–77.28) (54.20–69.99) (46.21–62.88)
158 194 221 190
94.30 91.81 90.50 89.47
80.18 73.49 61.32 58.38
130 395 525
96.42 (92.84–99.46) 82.78 (79.06–86.50) 86.10 (83.14–89.06)
80.00 (73.12–86.88) 60.24 (55.42–65.07) 65.71 (61.65–69.77)
382 381 763
92.67 (90.06–95.28) 92.02 (89.30–94.74) 92.40 (90.52–94.28)
(85.90–95.78) (80.50–93.04) (75.04–87.72) (71.53–85.31)
(90.68–97.92) (87.95–95.67) (86.63–94.37) (85.11–93.83)
(70.64–83.72) (67.28–79.70) (54.90–67.74) (51.37–65.39)
80.51 (75.46–83.56) 58.80 (53.86–63.74) 70.84 (66.58–73.10)
95% CI, 95% confidence interval.
Table 3 The distributions of HBV serological markers by different history of hepatitis B immunization in children aged 1–4 years in 2002 and 2006
2002 Vaccinated Unvaccinated Unknown 2006 Vaccinated Unvaccinated Unknown
Number investigated
HBsAg prevalence % (95% CI)
Anti-HBs prevalence % (95% CI)
Anti-HBc prevalence % (95% CI)
461 50 14
3.90 (2.14–5.67) 12.00 (2.99–21.01) 14.29 (2.00–43.00)
78.31 (74.55–82.07) 50.00 (48.55–75.45) 57.14 (31.22–83.07)
9.33 (6.67–11.98) 24.00 (12.16–35.84) 14.29 (2.00–43.00)
702 18 43
1.99 (0.96–3.03) 5.56 (0–16.14) 4.65 (0–10.95)
72.65 (69.35–75.95) 27.78 (7.09–48.47) 55.81 (40.97–70.66)
3.28 (1.96–4.59) 5.56 (0–16.14) 4.65 (2.12–4.69)
HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBs, antibody to hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core antigen; 95% CI, 95% confidence interval.
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J. Xiao et al. / International Journal of Infectious Diseases 16 (2012) e692–e696
of newborns is necessary to prevent perinatal HBV transmission.4,9 Since 1992, Guangdong has made strong efforts to establish universal infant immunization. Based on comparative studies of three serosurveys, the most dramatic finding is a significant decline in the prevalence of HBsAg among children born after HepB was recommended for routine infant immunization in 1992, and especially for children born after HepB was fully integrated into routine infant immunization in 2002. Conversely, the prevalence of anti-HBs for the population aged <15 years has increased from 37.21% in 1992 before HepB was recommended, to 61.87% in 2006. The present study showed that children aged 1 year had a significantly lower prevalence of HBsAg and higher prevalence of anti-HBs than older children. This could potentially be explained by higher HepB coverage among newborns. The successful introduction of HepB into the national immunization program has had a great impact on the prevalence of HBsAg among children. The results of the 2002 and 2006 surveys both affirm that universal vaccination of infants has contributed directly to the reduction in the prevalence of HBsAg. The prevalence of HBsAg was significantly lower and the prevalence of anti-HBs significantly higher among children who had been fully vaccinated than among unvaccinated children and among those with an unknown immunization status. These data are consistent with those of many studies in China,8,10–12 which have shown the prevalence of HBsAg to have declined significantly since the introduction of the hepatitis B vaccination programs. The decline in HBsAg among children in China can be attributed primarily to the impact of hepatitis B vaccination. Though there has been a decrease in the prevalence of HBV among young children in Guangdong Province similar to that reported in Shandong Province of China,12 the HBsAg prevalence has remained at a relatively high level in Guangdong, and this phenomenon is more serious in rural areas. Lots of data have revealed that the timely administration of the birth dose within 24 h after birth is highly effective for the prevention of hepatitis B among children born to highly infectious HBsAg-positive mothers, and it is strongly recommended that hepatitis B vaccination programs provide the birth dose in a timely manner.10,13–15 The 2006 survey showed that immunization coverage remained very low in rural areas and that children born in rural areas were more vulnerable to not receiving a timely birth dose or full immunization. Because a high proportion of women of childbearing age remain HBsAg- and hepatitis B e antigen (HBeAg)-positive, to achieve additional gains in reducing the hepatitis B risk among children, the authorities must continue to improve immunization, in particular the timely administration of birth doses, for these high-risk groups. This study has several limitations. First, the analysis of immunization coverage was based only on children aged <5 years, so we were unable to determine the relationship between the prevalence of HBsAg and immunization history among children aged 5–14 years. Second, the target population was children who had lived in a village for 6 months, and some floating (migrant) children and children who had been born outside of the birth control plan were excluded from the study. Therefore, there may be some bias in this study, such as overestimating immunization coverage or underestimating HBsAg prevalence. In the past 4 years, from 2007 to 2010, our monitoring data show that the immunization coverage rate has increased and that the prevalence of HBsAg has decreased steadily among children in Guangdong Province. A hepatitis B serological sampling survey was conducted in the province in 2010. The results showed that the
prevalence of HBsAg was 1.70% (9/529) among children aged <15 years and 0.60% (2/333) among children aged <7 years, which indicates the achievement of the national goal of a 1% HBsAg prevalence among children by 2010 and of the World Health Organization Regional Office for the Western Pacific hepatitis B reduction goal. However, larger scale studies are needed to confirm these results. In conclusion, Guangdong Province has successfully integrated HepB into routine immunization programs and this has had a very significant impact on decreasing the HBsAg carrier rate among children born after 1992. However, in rural areas, the HBsAg prevalence remains at a relatively high level among children, and the immunization coverage rate is still not high. To further reduce the prevalence of HBsAg, free vaccination of infants should be maintained and all infants should be targeted for a timely birth dose. In addition, Guangdong should focus on expanding coverage to all children aged <15 years. Acknowledgements We gratefully acknowledge the efforts of the Guangdong Province preventive medicine staff at all levels for implementing the mass hepatitis B vaccination campaign and for their help with blood sample collection during the surveys. Conflict of interest: No conflict of interest to declare. References 1. He J, Gu D, Wu X, Reynolds K, Duan X, Yao C, et al. Major causes of death among men and women in China. N Engl J Med 2005;353:1124–34. 2. Dai ZC, Qi GM. [Viral hepatitis seroepidemiological survey in Chinese population, 1992–1995 (part one)] (in Chinese). Beijing: China Science and Technical Documents Publishing House; 1997, p. 39–59. 3. Global progress toward universal childhood hepatitis B vaccination, 2003. MMWR Morb Mortal Wkly Rep 2003;52:868–70. 4. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis. BMJ 2006;332:328–36. 5. Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, et al. Epidemiological serosurvey of hepatitis B in China—declining HBV prevalence due to hepatitis B vaccination. Vaccine 2009;27:6550–7. 6. Progress in hepatitis B prevention through universal infant vaccination—China, 1997–2006. MMWR Morb Mortal Wkly Rep 2007;56:441–5. 7. Dai ZC, Qi GM. [Viral hepatitis seroepidemiological survey in Chinese population, 1992–1995 (part two)] (in Chinese). Beijing: China Science and Technical Documents Publishing House; 1997, p. 105–14. 8. Luo YX, Zhang ZJ, Li JJ, Li H, Cai HG, Fang L, et al. [Seroepidemiological investigation and analysis of virus hepatitis in Guangdong Province] (in Chinese). Chin J Vaccine Immunol 2005;11:89–92. 9. Ni YH, Huang LM, Chang MH, Yen CJ, Lu CY, You SL, et al. Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies. Gastroenterology 2007;132:1287–93. 10. Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, et al. Evaluation of the impact of hepatitis B vaccination among children born during 1992-2005 in China. J Infect Dis 2009;200:39–47. 11. Liu C, Li H, Gao L, Li F, Liang X, Yang K. Hepatitis B immunisation leads to the decline of hepatitis B virus prevalence in Gansu Province, China. Aust N Z J Public Health 2011;35:91–2. 12. Zhang L, Xu A, Yan B, Song L, Li M, Xiao Z, et al. A significant reduction in hepatitis B virus infection among the children of Shandong Province, China: the effect of 15 years of universal infant hepatitis B vaccination. Int J Infect Dis 2010;14:e483–8. 13. Da Villa G, Romano L, Sepe A, Iorio R, Paribello N, Zappa A, et al. Impact of hepatitis B vaccination in a highly endemic area of south Italy and long-term duration of anti-HBs antibody in two cohorts of vaccinated individuals. Vaccine 2007;25:3133–6. 14. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers. Cochrane Database Syst Rev 2006;(2):CD004790. 15. Zanetti AR, Mariano A, Romano L, D’Amelio R, Chironna M, Coppola RC, et al. Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study. Lancet 2005;366:1379–84.
Contents lists available at SciVerse ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Impact of hepatitis B vaccination among children in Guangdong Province, China Jianpeng Xiao a,b, Jikai Zhang a, Chenggang Wu a, Xiaoping Shao a, Guowen Peng a, Zhiqiang Peng a, Wenjun Ma a,b, Yonghui Zhang a, Huizhen Zheng a,* a b
Guangdong Provincial Center for Disease Control and Prevention, 176 Xingang Xi Road, Haizhu District, Guangzhou, China 510300 Guangdong Institute of Public Health, Guangzhou, China
A R T I C L E I N F O
S U M M A R Y
Article history: Received 5 January 2012 Accepted 14 May 2012
Objective: To evaluate the impact of the universal infant hepatitis B vaccination program on hepatitis B virus (HBV) infection in Guangdong Province, China. Methods: In 2006, a serosurvey was conducted in Guangdong Province among children aged <15 years, 14 years after the introduction of universal infant hepatitis B vaccination. The participants were selected by stratified, multi-stage random sampling. Demographic characteristics and hepatitis B vaccination history were collected by a questionnaire and a review of the vaccination records, and serum specimens were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis B surface antigen (anti-HBs) by ELISA. The prevalence rate of HBV serological markers and the rate of immunization coverage in this survey were compared with those of the 1992 and 2002 surveys. Results: A total of 1967 children aged <15 years participated in 2006. The prevalence rate of HBsAg decreased from 19.86% in the 1992 survey to 4.91% in the 2006 survey. The rates of three-dose and timely birth dose coverage of hepatitis B vaccine were 92.40% and 70.84%, respectively, among children born during the period 2002–2005. The prevalence of HBsAg was significantly lower among fully immunized children (1.99%) than among unvaccinated children (5.56%). Conclusions: Guangdong Province has successfully integrated the hepatitis B vaccine into routine immunization programs and this has had a very significant impact on decreasing the HBsAg carrier rate among children. ß 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: William Cameron, Ottawa, Canada Keywords: Prevalence Hepatitis B vaccination Vaccination coverage
1. Introduction Hepatitis B virus (HBV) infection is a serious health problem in China.1 In 1992, the national hepatitis serological survey revealed that the prevalence of hepatitis B surface antigen (HBsAg) was 9.75% in the population aged 1–59 years, and the rate in the 1–4 years age group was as high as the overall rate. Among the six regions of China, the south region had the highest HBsAg prevalence rate.2 Perinatal transmission is a major mode of HBV transmission in China.3,4 Therefore, China has made great efforts to establish universal infant immunization. The hepatitis B vaccine (HepB) was recommended for routine immunization of infants by the Ministry of Health in 1992. HepB was then fully integrated into the routine immunization program from 2002, and infants have been vaccinated without any charge since June 1, 2005.5,6
* Corresponding author. Tel.: +86 20 89023840; fax: +86 20 84459326. E-mail address: [email protected] (H. Zheng).
Guangdong Province is located in the south of China and is an area with a developed economy and an open culture. This is a highly populated province – the population was 95 million in 2006. The 1992 serological survey revealed shocking figures for the prevalence of HBsAg in Guangdong; this was as high as 17.85% in the general population, and 19.86% of children aged <15 years were found to carry HBV, making this the first ranking province in China.7 Following this survey, a long-term program to vaccinate newborns against HBV was started in Guangdong; more than 1.5 million newborns benefited from the HepB vaccination program each year. In addition to the national vaccination program, a massive HepB immunization campaign was carried out in Guangdong Province in 2001, in which children aged <18 years with incomplete HepB vaccination were required to obtain catchup injections. In 2002, another hepatitis B serological survey was conducted in Guangdong,8 10 years after the introduction of the universal infant HepB vaccination. Results showed that the HBsAg prevalence rate among children had decreased dramatically, from 19.86% to 8.56%. The latest provincial hepatitis B serological survey was conducted in 2006, 4 years after the routine immunization
1201-9712/$36.00 – see front matter ß 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijid.2012.05.1027
J. Xiao et al. / International Journal of Infectious Diseases 16 (2012) e692–e696
program. This survey aimed to determine the prevalence rates of HBV markers and HepB vaccination coverage among children born after universal hepatitis B vaccination was introduced, and to compare the results with those of the 1992 and 2002 surveys. 2. Materials and methods 2.1. Study population and sample method In September 2006, a cross-sectional serological survey was conducted in Guangdong Province, China. The target population was children aged <15 years at each of six national disease surveillance points (DSP), which were selected by the Chinese Center for Disease Control and Prevention (CDC) to be representative of the population of Guangdong Province. The six DSP could be divided into an urban group (Guangzhou, Shanwei, Yunfu) and a rural group (Shaoguan, Zhaoqing, Meizhou) (Figure 1). The subjects were selected by stratified, multi-stage random sampling in these six DSP. Three sub-districts in each urban district, two towns in each rural county, and one resident commission (village) in each sub-district (town) were selected randomly. In the selected resident commission (village), all children aged 1–4 years were interviewed and participants aged 5–14 years were chosen by systematic sampling. 2.2. Investigation A house-to-house investigation was completed by trained staff using a standard questionnaire. Written informed consent was provided by the parents of all children who participated in this survey. The child’s immunization status was recorded from their home immunization certificate, or if not available, the immunization information was recorded from the parent’s description. Otherwise, the immunization information was recorded as unvaccinated or unknown. Full vaccination was defined as receipt of three doses of HepB within 12 months, as documented by any immunization record. Timely birth-dose coverage was defined as receipt of the first dose of HepB within 24 h after birth.
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2.3. Specimen collection and laboratory testing The laboratory testing method was in accordance with a previous report.5 Blood samples were obtained from each study participant (4 ml for children aged 2 years and 2 ml for children aged <2 years). Serum was initially separated in the local laboratories and was subsequently transported to provincial laboratories. All serum specimens were sent to the National Hepatitis Laboratory for testing. HBsAg, antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc) were detected using an ELISA kit. 2.4. Data analysis All data were double-inputted using Epi Data 3.1 software and were checked for consistency and accuracy. The data were analyzed using SPSS 16.0 software (SPSS, Chicago, IL, USA). The rate was weighted by age, gender, and district on the basis of the data of the 2000 national census of Guangdong Province. 3. Results 3.1. Characteristics of the study population Overall, 1967 children aged <15 years participated in 2006. A total of 763 were aged 1–4 years and 1204 were aged 5–14 years. The sex and district distributions were as follows: 1078 males (54.8%) and 889 females (45.2%); 985 (50.1%) from urban areas and 982 (49.9%) from rural areas. 3.2. Distribution of HBV serological markers by age In the 2006 serological survey, the weighted prevalence rates of HBsAg, anti-HBs, anti-HBc, and HBV infection were 4.91%, 61.87%, 9.35%, and 18.00%, respectively, among children aged <15 years (Table 1). The HBsAg prevalence decreased steadily with decreasing age and the prevalence rate was lowest in 1-year-old children (0.64%) (Figure 2). The anti-HBs prevalence rate in 1-year-olds was
Figure 1. Geographic distribution of districts sampled in Guangdong Province, China.
Total
Rural
significantly higher than that for the other age groups. The highest prevalence rates of anti-HBc and HBV infection were observed in children aged 10–14 years. In comparison with the 1992 and 2002 surveys, which investigated 1032 and 1963 children aged <15 years, respectively, the HBsAg prevalence rate among children decreased dramatically from 19.86% to 4.91%, and the HBV infection rate decreased from 71.41% to 18.00%, while the anti-HBs rate increased from 37.21% to 61.87%. These trends were observed in all age groups (Figure 2). HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBs, antibody to hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core antigen; 95% CI, 95% confidence interval.
17.16 14.81–19.51 18.84 16.30–19.70 18.00 16.30–19.70 17.06 13.66–20.46 35.81 33.38–38.24 31.33 29.28–33.38 55.92 51.05–60.79 77.26 73.99–80.53 71.41 68.65–74.17 65.99 63.03–68.95 57.74 54.65–60.83 61.87 59.72–64.02 1.93 1.07–2.79 7.43 5.79–9.07 4.91 3.96–5.86 Urban/rural Urban
Female
40.11 35.31–44.91 35.01 31.29–38.73 37.21 34.26–40.16 1.97 0.71–3.32 10.91 9.33–12.49 8.56 7.32–9.80 8.55 5.81–11.29 23.4 20.10–26.70 19.86 17.43–22.29
75.41 71.51–79.31 60.83 58.35–63.31 68.01 65.95–70.07
45.05 40.17–49.93 60.01 56.19–63.83 53.59 50.55–56.63
13.22 10.15–16.29 25.50 23.29–27.71 22.57 20.72–24.42
4.57 3.27–5.87 14.15 11.97–16.33 9.35 8.06–10.64
18.46 16.14–20.78 17.44 14.95–19.93 32.32 29.57–35.07 30.07 26.99–33.15 74.64 71.02–78.26 67.65 63.45–71.85 63.27 60.39–66.15 60.18 56.96–63.40 Sex Male
5.19 3.87–6.51 4.05 2.75–6.35
37.59 33.56–41.62 36.76 32.43–41.09 10.05 8.28–11.82 6.60 4.93–8.27 23.56 20.03–27.09 15.55 12.29–18.81
66.12 63.34–68.90 69.95 66.87–73.03
55.58 51.45–59.71 51.26 46.77–55.75
23.16 20.68–25.64 21.82 19.04–24.60
9.37 7.63–11.11 9.34 7.43–11.25
2006 2002 1992 2006 2002
Anti-HBs prevalence,%; 95% CI
1992 2002 1992
2006 HBsAg prevalence,%; 95% CI Group
Table 1 Prevalence rate of HBV markers among children aged 1–14 years in Guangdong Province, in 1992, 2002, and 2006
Anti-HBc prevalence,%; 95% CI
2006
1992
2002
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HBV infection prevalence,%; 95% CI
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3.3. Distribution of HBV serological markers by sex and district HBsAg prevalence was significantly higher for males than females (5.19% vs. 4.05%, p < 0.05) and this phenomenon was also observed in both the 1992 and 2002 surveys (Table 1). The HBsAg prevalence among persons living in rural areas was higher than among those living in urban areas (7.43% vs. 1.93%, p < 0.01) and the prevalence of anti-HBs was higher in urban than in rural areas (65.99% vs. 57.74%, p < 0.05). Similarly, these phenomena were also observed in both the 1992 and 2002 surveys (Table 1). 3.4. Immunization coverage of hepatitis B vaccine for children aged <5 years The survey found that immunization records were not well kept during the 1990s; the HepB vaccination history for those with no written records was obtained by interviewing the child’s parents, so the immunization history in a large portion of children aged >10 years was undefined. Thus, the analysis of immunization coverage was based only on children aged <5 years. For children born during the period 2002–2005, the rates of weighted three-dose and timely birth dose coverage of HepB were 92.40% and 70.84%, respectively. The coverage rate increased steadily with decreasing age. In addition, although there was no significant difference in the rates of three-dose coverage between urban and rural areas, the prevalence of timely birth dose coverage was higher in urban than in rural areas (80.51% vs. 58.80%, p < 0.05). Compared to the same age group in the 2002 survey, the rates of three-dose and timely birth dose coverage of HepB increased from 86.10% to 92.40%, and from 65.71% to 70.84%, respectively (Table 2). 3.5. Prevalence of HBsAg and other HBV markers and immunization history Different histories of hepatitis B immunization led to obvious differences in the distributions of HBV prevalence. The prevalence of HBsAg was significantly lower among children who had been fully vaccinated than among unvaccinated children and among those with unknown immunization status. The prevalence of HBsAg was 1.99% among children born during 2002–2005 who received the full three-dose immunization series, while among children who had not been immunized, the prevalence of HBsAg was 5.56%. The prevalence of anti-HBs was higher among fully immunized children (72.65%) than among unvaccinated children (27.78%). The prevalence of anti-HBc was significantly lower among fully immunized children (3.28%) than among unvaccinated children (5.56%). A comparison between the 2002 and 2006 survey results showed that they were in accordance with each other (Table 3). 4. Discussion Endemic HBV infection is a serious health problem in China, especially in Guangdong Province.7 Vaccination is considered the most cost-effective way to control hepatitis B, and immunization
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Figure 2. Comparison of the age-specific prevalence rate of (A) HBsAg, (B) anti-HBs, (C) anti-HBc, and (D) HBV infection among children aged 1–14 years in 1992, 2002, and 2006 in Guangdong Province.
Table 2 Immunization coverage of hepatitis B vaccine for children aged 1–4 years in 2002 and 2006 2006
2002 Age, years
Number investigated
Three dose coverage % (95% CI)
Timely birth dose coverage % (95% CI)
Number investigated
Three dose coverage % (95% CI)
Timely birth dose coverage % (95% CI)
1 2 3 4 Urban/rural Urban Rural Total
131 112 145 137
90.84 86.77 81.38 78.42
77.31 68.69 62.10 54.55
(70.14–84.48) (60.10–77.28) (54.20–69.99) (46.21–62.88)
158 194 221 190
94.30 91.81 90.50 89.47
80.18 73.49 61.32 58.38
130 395 525
96.42 (92.84–99.46) 82.78 (79.06–86.50) 86.10 (83.14–89.06)
80.00 (73.12–86.88) 60.24 (55.42–65.07) 65.71 (61.65–69.77)
382 381 763
92.67 (90.06–95.28) 92.02 (89.30–94.74) 92.40 (90.52–94.28)
(85.90–95.78) (80.50–93.04) (75.04–87.72) (71.53–85.31)
(90.68–97.92) (87.95–95.67) (86.63–94.37) (85.11–93.83)
(70.64–83.72) (67.28–79.70) (54.90–67.74) (51.37–65.39)
80.51 (75.46–83.56) 58.80 (53.86–63.74) 70.84 (66.58–73.10)
95% CI, 95% confidence interval.
Table 3 The distributions of HBV serological markers by different history of hepatitis B immunization in children aged 1–4 years in 2002 and 2006
2002 Vaccinated Unvaccinated Unknown 2006 Vaccinated Unvaccinated Unknown
Number investigated
HBsAg prevalence % (95% CI)
Anti-HBs prevalence % (95% CI)
Anti-HBc prevalence % (95% CI)
461 50 14
3.90 (2.14–5.67) 12.00 (2.99–21.01) 14.29 (2.00–43.00)
78.31 (74.55–82.07) 50.00 (48.55–75.45) 57.14 (31.22–83.07)
9.33 (6.67–11.98) 24.00 (12.16–35.84) 14.29 (2.00–43.00)
702 18 43
1.99 (0.96–3.03) 5.56 (0–16.14) 4.65 (0–10.95)
72.65 (69.35–75.95) 27.78 (7.09–48.47) 55.81 (40.97–70.66)
3.28 (1.96–4.59) 5.56 (0–16.14) 4.65 (2.12–4.69)
HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBs, antibody to hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core antigen; 95% CI, 95% confidence interval.
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of newborns is necessary to prevent perinatal HBV transmission.4,9 Since 1992, Guangdong has made strong efforts to establish universal infant immunization. Based on comparative studies of three serosurveys, the most dramatic finding is a significant decline in the prevalence of HBsAg among children born after HepB was recommended for routine infant immunization in 1992, and especially for children born after HepB was fully integrated into routine infant immunization in 2002. Conversely, the prevalence of anti-HBs for the population aged <15 years has increased from 37.21% in 1992 before HepB was recommended, to 61.87% in 2006. The present study showed that children aged 1 year had a significantly lower prevalence of HBsAg and higher prevalence of anti-HBs than older children. This could potentially be explained by higher HepB coverage among newborns. The successful introduction of HepB into the national immunization program has had a great impact on the prevalence of HBsAg among children. The results of the 2002 and 2006 surveys both affirm that universal vaccination of infants has contributed directly to the reduction in the prevalence of HBsAg. The prevalence of HBsAg was significantly lower and the prevalence of anti-HBs significantly higher among children who had been fully vaccinated than among unvaccinated children and among those with an unknown immunization status. These data are consistent with those of many studies in China,8,10–12 which have shown the prevalence of HBsAg to have declined significantly since the introduction of the hepatitis B vaccination programs. The decline in HBsAg among children in China can be attributed primarily to the impact of hepatitis B vaccination. Though there has been a decrease in the prevalence of HBV among young children in Guangdong Province similar to that reported in Shandong Province of China,12 the HBsAg prevalence has remained at a relatively high level in Guangdong, and this phenomenon is more serious in rural areas. Lots of data have revealed that the timely administration of the birth dose within 24 h after birth is highly effective for the prevention of hepatitis B among children born to highly infectious HBsAg-positive mothers, and it is strongly recommended that hepatitis B vaccination programs provide the birth dose in a timely manner.10,13–15 The 2006 survey showed that immunization coverage remained very low in rural areas and that children born in rural areas were more vulnerable to not receiving a timely birth dose or full immunization. Because a high proportion of women of childbearing age remain HBsAg- and hepatitis B e antigen (HBeAg)-positive, to achieve additional gains in reducing the hepatitis B risk among children, the authorities must continue to improve immunization, in particular the timely administration of birth doses, for these high-risk groups. This study has several limitations. First, the analysis of immunization coverage was based only on children aged <5 years, so we were unable to determine the relationship between the prevalence of HBsAg and immunization history among children aged 5–14 years. Second, the target population was children who had lived in a village for 6 months, and some floating (migrant) children and children who had been born outside of the birth control plan were excluded from the study. Therefore, there may be some bias in this study, such as overestimating immunization coverage or underestimating HBsAg prevalence. In the past 4 years, from 2007 to 2010, our monitoring data show that the immunization coverage rate has increased and that the prevalence of HBsAg has decreased steadily among children in Guangdong Province. A hepatitis B serological sampling survey was conducted in the province in 2010. The results showed that the
prevalence of HBsAg was 1.70% (9/529) among children aged <15 years and 0.60% (2/333) among children aged <7 years, which indicates the achievement of the national goal of a 1% HBsAg prevalence among children by 2010 and of the World Health Organization Regional Office for the Western Pacific hepatitis B reduction goal. However, larger scale studies are needed to confirm these results. In conclusion, Guangdong Province has successfully integrated HepB into routine immunization programs and this has had a very significant impact on decreasing the HBsAg carrier rate among children born after 1992. However, in rural areas, the HBsAg prevalence remains at a relatively high level among children, and the immunization coverage rate is still not high. To further reduce the prevalence of HBsAg, free vaccination of infants should be maintained and all infants should be targeted for a timely birth dose. In addition, Guangdong should focus on expanding coverage to all children aged <15 years. Acknowledgements We gratefully acknowledge the efforts of the Guangdong Province preventive medicine staff at all levels for implementing the mass hepatitis B vaccination campaign and for their help with blood sample collection during the surveys. Conflict of interest: No conflict of interest to declare. References 1. He J, Gu D, Wu X, Reynolds K, Duan X, Yao C, et al. Major causes of death among men and women in China. N Engl J Med 2005;353:1124–34. 2. Dai ZC, Qi GM. [Viral hepatitis seroepidemiological survey in Chinese population, 1992–1995 (part one)] (in Chinese). Beijing: China Science and Technical Documents Publishing House; 1997, p. 39–59. 3. Global progress toward universal childhood hepatitis B vaccination, 2003. MMWR Morb Mortal Wkly Rep 2003;52:868–70. 4. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis. BMJ 2006;332:328–36. 5. Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, et al. Epidemiological serosurvey of hepatitis B in China—declining HBV prevalence due to hepatitis B vaccination. Vaccine 2009;27:6550–7. 6. Progress in hepatitis B prevention through universal infant vaccination—China, 1997–2006. MMWR Morb Mortal Wkly Rep 2007;56:441–5. 7. Dai ZC, Qi GM. [Viral hepatitis seroepidemiological survey in Chinese population, 1992–1995 (part two)] (in Chinese). Beijing: China Science and Technical Documents Publishing House; 1997, p. 105–14. 8. Luo YX, Zhang ZJ, Li JJ, Li H, Cai HG, Fang L, et al. [Seroepidemiological investigation and analysis of virus hepatitis in Guangdong Province] (in Chinese). Chin J Vaccine Immunol 2005;11:89–92. 9. Ni YH, Huang LM, Chang MH, Yen CJ, Lu CY, You SL, et al. Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies. Gastroenterology 2007;132:1287–93. 10. Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, et al. Evaluation of the impact of hepatitis B vaccination among children born during 1992-2005 in China. J Infect Dis 2009;200:39–47. 11. Liu C, Li H, Gao L, Li F, Liang X, Yang K. Hepatitis B immunisation leads to the decline of hepatitis B virus prevalence in Gansu Province, China. Aust N Z J Public Health 2011;35:91–2. 12. Zhang L, Xu A, Yan B, Song L, Li M, Xiao Z, et al. A significant reduction in hepatitis B virus infection among the children of Shandong Province, China: the effect of 15 years of universal infant hepatitis B vaccination. Int J Infect Dis 2010;14:e483–8. 13. Da Villa G, Romano L, Sepe A, Iorio R, Paribello N, Zappa A, et al. Impact of hepatitis B vaccination in a highly endemic area of south Italy and long-term duration of anti-HBs antibody in two cohorts of vaccinated individuals. Vaccine 2007;25:3133–6. 14. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers. Cochrane Database Syst Rev 2006;(2):CD004790. 15. Zanetti AR, Mariano A, Romano L, D’Amelio R, Chironna M, Coppola RC, et al. Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study. Lancet 2005;366:1379–84.