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Saturday, 6th of March 2010 Print
CSU 26/2010: TWO ON HEP B
Writing in the Bulletin of the World Health Organization, Rani and colleagues make the case for time bound goals for hep B control. Of the six WHO regions, Western Pacific is the first to have set such a goal.
From the authors' discussion:
'To date, most supranational time-bound disease-specific goals have focused on eradicable diseases and were driven by the cost savings that could be achieved after eradication. The example of the regional hepatitis B control goal in the WPR shows that setting a supranational time-bound disease control goal can help generate a sense of political urgency and accelerate efforts to control diseases that pose important public health problems but are not necessarily eradicable. Whereas for disease eradication, the target date relates to the time needed to implement a large-scale intervention involving immunization or drug treatment to wipe out a pathogen, the target date for disease control relates to the time needed to bring the programme performance up to a desirable level.

'If a supranational goal is to achieve its intended impact, it should be based on technical evidence and have clearly defined programme strategies, process indicators and a measurable outcome goal, and there should be a definite time-line for achieving the goal. Equal emphasis needs to be placed on the final outcome and the process used to achieve it. The proposal that achievement of the hepatitis B control goal should be independently certified using well-defined criteria is innovative, and has previously been applied only to disease-eradication goals. The independent certification process will involve few additional costs and regular reporting of results will maintain both a sense of urgency and pressure to improve performance.'

It should be noted that WPR is much farther along with polio, measles and tetanus than most of the other regions. Not all regions are in a strong position to move quickly towards hep B control goals.
The Western Pacific region could not have set a timebound regional goal but for the large scale hep B introduction done in China, here reviewed for the first time in English by Zhou and colleagues. The work of hep B prevention in a country with high baseline levels of endemicity is not completed, but well begun, as judged from the results of a 2006 serosurvey  covering all of mainland China: ' the HBsAg prevalence was 7.2% in general population and 1.1% in children under 5 years of age.40 Given the huge population in China, a reduction of the overall positive rate from 10.0% to 7.2% implies that over 30 million persons have been protected against chronic HBV infection.'
For the world’s most populous country, hep B vaccination has been a massive undertaking. The authors cover several unique features in the roll-in:


  • the willingness of the GAVI Alliance to finance hep B vaccination in remote and underserved areas of the PRC.


  • the ‘out of cold chain’ use of the relatively heat stable hep B vaccine, documented in authors’ references 27-30


  • Technology transfer from Merck to permit set-up of local vaccine production


Good reading.




The authors’ abstract:

Objective  To review the implementation of mass vaccination of hepatitis B vaccine and its critical role in prevention of hepatitis B virus infection in China.
Data sources  The data were mainly from PubMed, China Hospital Knowledge Database, and other popular Chinese journals published from 1980 to 2008. The search term was “hepatitis B vaccine”.
Study selection  Original studies conducted in China and critical reviews authored by principal investigators in the field of hepatology in China were selected.
Results  Chinese investigators started to develop hepatitis B vaccine in late 1970s. The first home-made plasma-derived vaccine became available in 1986, which has been completely replaced by the domestically produced recombinant (yeast or Chinese hamster ovary cell) vaccine since 2001. China health authority recommended vaccinating all infants in 1992. From then on, China has put tremendous efforts in implementation of mass vaccination. The overall coverage of hepatitis B vaccine in infants has increased steadily and reached more than 95.0% in urban and 83.0%–97.0% in rural areas. The chronic HBV carrier rate in children <10 years of age decreased from 10.0% before the mass vaccination to 1.0%–2.0% in 2006, and that in general population decreased from 10.0% to 7.2%; overall, the nationwide mass hepatitis B vaccination has reduced more than 30 million of chronic HBV infections and HBV related severe sequlae.
Conclusion  The Chinese successful experience in control of hepatitis B by mass vaccination offers an example for any unindustrialized country whoever is committed to control this disease.


Chinese Medical Journal, 2009, Vol. 122 No. 1 : 98-102

Vaccination against hepatitis B: the Chinese experience

ZHOU Yi-hua, WU Chao, ZHUANG Hui

ZHOU Yi-hua Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China; WU Chao Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China; ZHUANG Hui Department of Microbiology, Peking University Health Science Center, Beijing 100191, China

Correspondence to: ZHUANG Hui  Department of Microbiology, Peking University Health Science Center, Beijing 100191, China  (Tel:86-10-62092221 Fax:86-10-62091617 Email: zhuanghu@public.bj.cninfo.net )


Hepatitis B virus (HBV) infection is a serious health problem worldwide. Globally, it is estimated that over 2 billion persons have evidence of past HBV infection, more than 350 million are chronic carriers, and some one million deaths annually are attributed to HBV-related diseases. One of the distinct characteristics of HBV infection is that the chronicity greatly depends upon the age: infections occurred in neonates and in childhood result in 80%–90% and 30%–50% chronic carriage respectively; in contrast, only 5%–10% of infections become chronic in adolescence and adulthood.1 Once chronic infection is established, HBV may persist in the liver for lifetime,2,3 which not only causes severe HBV-related sequelae such as cirrhosis and hepatocellular carcinoma but also constitutes the reservoir of the virus.

HBV infection is highly endemic in China; transmission during the perinatal period and the early childhood is the most important infection mode.4 Thus, prevention of HBV infection in infants and preschool children through vaccination with hepatitis B vaccine is the most critical strategy to control HBV infection in China. Chinese health authorities have put the prevention of HBV infection as a high priority, and China is one of the two first countries in the developing world to attempt to control HBV infection by mass immunization of hepatitis B vaccine.5


The first hepatitis B vaccine, derived from human carrier plasma, was licensed in the US in 1981. Since having the largest population in the world, China must produce its own vaccine against hepatitis B; extensive investigations on the development of the vaccine were conducted using HBsAg purified from human carriers.6-8 A locally produced plasma-derived hepatitis B vaccine in China became available in 1986. The vaccine, which is used by intramuscular injection with 3 doses, usually on a schedule of 0, 1, and 6 months respectively (Table), was proved to be safe and highly effective for preventing HBV infection in infants born to HBV carrier mothers in clinical trials9-11 as reported in other countries or regions. The home-made vaccine also showed to be long-term effective, for at least up to 20 years.12 Concurrent use of the vaccine and hepatitis B immunoglobulin (HBIG) showed better protection in neonates born to mothers positive for both HBsAg and hepatitis B e antigen (HBeAg).

Since supplies of the carrier plasma were inadequate to produce sufficient vaccine for mass vaccination, the domestically made vaccine, at the beginning, was exclusively used for high risk groups, particularly for neonates born to HBV carrier mothers. To overcome the shortage of the HBV carrier plasma and potential risk of the plasma-derived vaccine, China authorities initiated the projects to develop hepatitis B vaccine composed of purified recombinant HBsAg produced from recombinant expression systems.13 The mammalian cell produced HBsAg was proved to be highly immunogenic in human and proved to be effective in prevention of mother-to-infant transmission as did the plasma antigen.14 The Chinese hamster ovary (CHO) cell HBsAg expression system was licensed to produce recombinant CHO hepatitis B vaccine in 1996.15 Meanwhile, Chinese vaccine makers were granted to produce recombinant (yeast) hepatitis B vaccine through transfer of technology from Merck & Dohme Co. The recombinant vaccine produced in China was proved to be highly effective in clinical trials as the plasma vaccine did, and was substituted for the plasma antigen to prepare hepatitis B vaccine. Since 2001, all hepatitis B vaccine used in China has been composed of recombinant (yeast or CHO) HBsAg (Table). Another homemade yeast (hansenula polymorpha) recombinant vaccine was licensed in China in 2004.
The Ministry of Health of China recommended in 1992 that hepatitis B vaccine be routinely used for neonates as a part of China′s Planned Vaccination Program, however, the nationwide use of hepatitis B vaccine had been hampered by several factors: first was the cost of vaccine charged to infants′ parents; second was the lack of public awareness of the vaccine; third was that the vaccine supplies were not sufficient or were inadequately distributed. Thus, the overall coverage was low. In rural areas, the coverage rates ranged from 18.1% to 50.0% in 1993–1994, depending upon the wealth,16,17 while the coverage in cities was as high as 96.0%–100%.18 A nationwide survey conducted in 1999 showed that, among children born in 1997, while the overall coverage reached to 70.7% in the 31 mainland provinces, the coverage in 13 provinces, mostly in China's western regions, were less than 50.0%, with the lowest of 7.8% in Tibet;19 the three reasons mentioned above were still attributed to the inadequate coverage.

To raise the hepatitis B vaccine coverage, beginning in 2002, the China health authorities provided all neonates with free hepatitis B vaccine but charged their parents for the injection service fee. Meanwhile, the Ministry of Health of China initiated a project together with the Global Alliance for Vaccines and Immunization to vaccinate free-of-charge all neonates in 12 China′s western provinces and in the poorest counties of 10 other provinces. The 5-year project covered 1031 out of the total 2862 counties and 470 million population, with vaccination of 5.84 million of neonates annually.20 A survey in 11 of the 12 western provinces showed that the average timely birth-dose coverage reached to 88.6% among neonates born in township hospitals and 89.8%–96.6% among those born in city and province hospitals in 2005,21 whereas the timely birth-dose coverage in neonates was 46.5% in township hospitals and 61.2% in city and province hospitals in the same region in 1998 and 1999.22 Accordingly, the coverage with 3 doses of the vaccine also increased significantly.23 The data indicate that providing the vaccine with no charges would improve the both timely birth-dose and full vaccination coverage.

In 2005, China authority set up a novel vaccine regulation that all vaccines, including hepatitis B vaccine, listed in the China's National Immunization Program are free of charge to all neonates and infants. Thereafter, while the hepatitis B vaccine coverage in neonates in cities maintained to approximately 95.0%, the coverage in most rural areas increased to 83.5%–96.5%,24 significantly higher than the rates before the regulation was implemented.

Since China has a vast, geographically diverse territory and world′s largest population, many residents are living in remote or isolated areas with poor health services. The hepatitis B vaccine coverage in these areas was much lower than that in other areas. A survey in Huangnan County, which is located in Qinghai Province and over 3000 m above the sea level, showed that, in 2004, the timely birth-dose coverage was only 42.6% and the coverage with 3 doses of the vaccine was only 46.5%.25 After reinforcing health education, training the health providers, improving transportation and increasing the percentage of neonates delivered in hospitals, strengthening the coordination among village doctors, vaccinators, midwives and mothers, setting up regular vaccine distributions to remote and isolated areas, and using auto-disposable syringes for all immunization injections, the timely birth-dose coverage increased to 75.0% in 2005 in the same areas.26

Another practically effective means to raise the coverage in the remote areas is to preserve the hepatitis B vaccine at ambient temperature, rather than in cold-chain as usually required, which is not affordable by the local health service departments in some remote or isolated areas. It was reported that the vaccine kept at room temperature for one week to two months has same immunogenicity as the vaccine kept in cold chain.27–29 Thus, keeping the vaccine at ambient temperature makes it feasible to distribute the vaccine appropriately and to increase the on time coverage in the remote areas.29,30

A nationwide seroprevalence survey conducted in 1979, in which HBsAg was detected with reverse passive hemagglutination assay in sera of 266 728 residents from all provinces except for Taiwan across the country, showed that the overall HBsAg positive rate was 8.8% (3.8%–16.8%) and the rate in rural area was higher than in cities (10.2% vs 7.9%).31 In children under 1 year of age, the prevalence of HBsAg ranged from 3.8% to 7.0%, and the prevalence reached the peak with 12.6% in 5 years old children in rural areas and with 9.1% at 9 years old in cities.31 Other national surveys with the more sensitive radioactive immunoassay in 4039 sera from five provinces and in 10 484 sera from four provinces revealed HBsAg carriage rate was 10.3% and 10.1% respectively.32,33 These data were validated by subsequent numerous investigations conducted by local health departments. Generally, some 10% of Chinese populations before mass hepatitis B vaccination were chronic HBsAg carriers.

However, the epidemiologic profile of HBV infection in China is changing. Although the overall HBsAg seropositive rate showed no significant decline before 2000, the carrier rates in vaccinated children decreased significantly. In Beijing, while the vaccine coverage rate reached to 91.5% in 1993 and increased to 99.3% in 1997, the HBsAg carrier rate was only 0.4%–0.5% in children under 3 years old, considerable lower than 4.3% in 1979 and 1980;34 in 2000, the carrier rate in persons aged 10–19 years in Beijing was 1.4%, whereas the rate in the same age group in 1992 was 6.3%.35 A survey in 1271 children aged 3–4 years in 4 cities conducted in 1997 showed that the vaccine coverage rate in urban area was 95.1% and that in suburban area was 81.3%, with an average of 81.8% (61.8%–100%); none of the children in 4 urban areas became HBsAg carrier while 3.4% of the children in suburban became HBsAg carriers.36 The scenario in other regions is similar. In 1994, 2 years after the initiation of mass hepatitis vaccination, a follow-up survey in China′s southern region, Guangxi where the prevaccination prevalence was available, showed that the HBsAg positive rate in 1459 vaccinated children aged 1–2 years old was as low as 1.7%, compared with 7.9% in 1986 before vaccination.37 An investigation in China′s central region, Xiangtan, Hunan province, conducted in 2000 showed that of 2882 vaccinated children ≤15 years old (born after 1985), only 32 (1.1%) were positive for HBsAg, significantly lower than the carrier rate of 10.3% in 1984, and the HBsAg carriage rate in unvaccinated children in the same region also reduced significantly (3.3%).38 Meanwhile, the overall infection rates (positive for HBsAg and/or anti-HBc) in each age group remains to be relatively constant, compared with the increased prevalence with age (Figure 1).38 Together, the data demonstrate that mass vaccination with hepatitis B vaccine can not only protect vaccinated persons but also reduce the possible horizontal infection in the unvaccinated subjects.
The population based hepatitis B vaccination in rural areas has also been successful. The mass immunization program in some villages of Zhengding County, Hebei Province started in 1986; all infants were accessible to hepatitis B vaccine. A seroprevalence study, which was conducted among 10 010 residents of eight villages who were ≥1 year of age, displayed that the HBsAg carrier in general population was reduced from 8.6% in 1983 to 5.3% in 2005; particularly, the reduction in young age groups was striking (Figure 2).39 A more recent seroepidemiologic study across the mainland China conducted in 2006 showed the HBsAg prevalence was 7.2% in general population and 1.1% in children under 5 years of age.40 Given the huge population in China, a reduction of the overall positive rate from 10.0% to 7.2% implies that over 30 million persons have been protected against chronic HBV infection.



The implementation of universal infant vaccination against hepatitis B in China is being rewarded by reduction in incidences of HBV infections and chronic carrier rate. The success is the result of national continuous efforts to control this disease: designation of hepatitis B as one of the four high priority diseases for national control, domestically produced vaccines, effective coordination among health departments and the other relevant agencies, new national vaccination regulations, strong international partnerships, and dedication of countless healthcare workers are most critical for the achievement. The Chinese experience highlights the importance of hepatitis B vaccination in control of HBV infection, and indicates that HBV infection can be controlled also in any unindustrialized country whoever is committed to control this disease.


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