Decreasing incidence of hepatocellular carcinoma among children following universal hepatitis B immunization

Abstract: Hepatocellular carcinoma (HCC) is one of the 10 most common malignant tumors worldwide. Chronic infection with hepatitis B or C virus is closely related to hepatocarcinogenesis. The outcome of current therapies for HCC is not satisfactory. Prevention is the best way to control HCC. Among the various strategies of HCC prevention, immunization against hepatitis B virus infection is the most effective. Universal hepatitis B immunization has proved to be effective in reducing the incidence of HCC to 1/4–1/3 of that in children born before the hepatitis B vaccination era in Taiwan. The problems we face in achieving global control of hepatitis‐related HCC include: (1) no effective vaccine for the prevention of hepatitis C and its related HCC; (2) no immunization program for hepatitis B in areas with inadequate resources; (3) poor compliance to the immunization program as a result of ignorance, anxiety, or poverty; and (4) vaccine failure. Integration of the hepatitis B vaccination program into the expanded program of immunization for all infants throughout the world will be most urgent and important for HCC control. The reduction of the incidence of HCC will be seen in adults 30–40 years of age after the launch of the universal hepatitis B vaccination program. This concept of cancer vaccine can be applied to other infectious agents and their related cancers.     

Vaccination against hepatitis B: current challenges for Asian countries and future directions

AIMS: To review the current status of hepatitis B immunization programmes as well as future issues concerning hepatitis B immunization in Asian countries. METHODS: Pertinent literature was identified via in-house and MEDLINE (1980-99) searches and references cited in published articles. Articles within the Proceedings of the IX Triennial International Symposium on Viral Hepatitis and Liver Disease provided valuable state-of-the-art resource data. RESULTS: Chronic hepatitis B infection is responsible for 75-90% of primary hepatocellular carcinoma, one of the 10 most common cancers worldwide. Hepatitis B and its chronic sequelae can potentially be eradicated through vaccines that have been shown to be 95-99% efficacious in preventing development of the disease or the carrier state in immunized infants. Approximately 75% of the world's hepatitis B carriers live in Asian countries wherein wide variations in immunization strategies exist. Vaccination programmes in hyperendemic Asian countries have elicited decreases in the incidence of acute and chronic infections as well as a decrease in chronic carriers in the unvaccinated population. Decreases in the incidence of hepatocellular carcinoma have been recorded in Taiwan and Singapore after at least 10 years of universal hepatitis B immunization programmes. CONCLUSIONS: In Asian countries currently without nationwide hepatitis B programmes, utilization of the existing vaccination infrastructure for administration of other World Health Organization Expanded Programme on Immunization vaccines will provide the most economical and efficient means of administration of the hepatitis B vaccine.     

Two decades of universal hepatitis B vaccination in taiwan: impact and implication for future strategies

BACKGROUND & AIMS: Following the world's first successful implementation of a universal hepatitis B virus (HBV) vaccination program for infants in Taiwan 20 years ago, we performed this study to evaluate the long-term protection afforded by HBV vaccination and to rationalize further prevention strategies. METHODS: HBV seromarkers, including hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) and core antigen (anti-HBc), were studied in 18,779 subjects from neonates to adults below 30 years of age in 2004. The birth cohort effect was evaluated by comparing the results of the same birth cohorts at different ages among this survey and the previous 1984, 1989, 1994, and 1999 surveys. RESULTS: The seropositive rates for HBsAg, anti-HBs, and anti-HBc were 1.2%, 50.5%, and 3.7%, respectively, in those born after the vaccination program (<20 years of age) in 2004. A positive maternal HBsAg status was found in 89% of the HBsAg seropositive subjects born after the vaccination program. The absence of an increase in HBsAg seropositive subjects at different ages in the same birth cohorts born after the vaccination program implied no increased risk of persistent HBV infection with aging. CONCLUSIONS: Universal HBV vaccination provides long-term protection up to 20 years, and a universal booster is not indicated for the primary HBV vaccinees before adulthood. Maternal transmission is the primary reason for vaccine failure and is the challenge that needs to be addressed in future vaccination programs. This may include an appropriate hepatitis B immunoglobulin administration strategy for high-risk infants and involve efforts to minimize noncompliance.     

Waning-off effect of serum hepatitis B surface antibody amongst Taiwanese university students: 18 years post-implementation of Taiwan's national hepatitis B vaccination programme

Summary. Hepatitis B virus (HBV) infection and its sequelae remain a major health problem for Taiwan. The national hepatitis B (HB) vaccination programme was first launched in 1984 to combat the spread of this infection. This study examined the status of HBV infection amongst students at a Taiwanese university in 2005, 18 years after the implementation of a nation‐wide mass HB vaccination programme. In 2005, 5875 new university entrants, who were born during the period 1 July 1976 to 30 June 1988, were subdivided into one of 12 one‐year‐interval birth‐year cohorts. Each student was individually tested for serum hepatitis B surface antigen (HBsAg), Antibody to hepatitis B surface antigen (anti‐HBs) and antibody to hepatitis B core antigen (anti‐HBc) status. We observed a declining trend of past exposure to HB infection from 48.7% (1976 birth‐year cohort) to 5.2% (1987 birth‐year cohort). The prevalence of chronic HB infection also declined from 14.5% (1976 birth‐year cohort) to 1.9% (1987 birth‐year cohort). The prevalence of persistent HB immunity through (earlier) active vaccination declined from 72% (1984 birth‐year cohort) to 41.6% (1987 birth‐year cohort). The prevalence of HB infection‐naïve individuals increased from 18.2% (1984 birth‐year cohort) to 53.1% (1987 birth‐year cohort). This study demonstrates that as the implementation of the mass HB vaccination programme in 1984, the incidence of HB infection in Taiwan has declined, although a ‘waning‐off’ effect of serum anti‐HBs to low or undetectable levels, which may not provide protection, amongst this student population has arisen, 18 years following the implementation of the nation‐wide HB vaccination programme. Such a situation may mean that these individuals may not be effectively protected against future HB infection. A booster dose of HB vaccine, given 18 years following HB vaccination, perhaps even earlier, should be considered.     

Long-term effectiveness of infancy low-dose hepatitis B vaccine immunization in Zhuang minority area in China

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Towards the eradication of hepatitis B in Taiwan

Viral hepatitides are important public health problems in humans. The etiologic agents were not identified until 1965, when Baruch S. Blumberg found the relationship of Australia antigen to serum hepatitis. The antigen was found to be the surface antigen of the hepatitis B virus (HBV). This observation launched a new era in the diagnosis, prevention and treatment of hepatitis B. Over 15-20 years, the natural history of HBV infection was elucidated, and more importantly, an effective vaccine became available. The routes of transmission were also made clear, rendering effective interruption of the transmission possible. The vaccine together with effective interruption of the transmission contributed greatly to the control of HBV infection. However, these measures do very little for those who have already been chronically infected. Fortunately, specific therapies against chronic hepatitis B started to appear about 10-15 years before, and the treatments have improved substantially in the last few years. Although far from perfect, effective means to treat those who are chronically infected now exist. In Taiwan, acute and chronic liver diseases were rampant as early as the beginning of the last century. Studies around 1975, showed an extremely high prevalence of chronic hepatitis B infection in the general population (15-20%), and 80-90% of the chronic liver diseases and hepatocellular carcinoma were caused by chronic infection with the HBV. This important health problem caught the attention of the government in the late 1970s, and a government-sponsored control program was finalized in 1981. Accordingly, a mass vaccination program against hepatitis B, primarily aiming at immunizing newborn infants, was launched on July 1, 1984. Twenty years after implementation of the program, the hepatitis B carrier rate in children covered by the program decreased by 85%, from ～ 15% to <1%. Most importantly, the deadly sequela of hepatocellular carcinoma in the vaccinees was also found to decrease in parallel. This is the first time that a human cancer was prevented by vaccination. Despite the success, there are still some who were born after implementation of the program but were not prevented from developing chronic hepatitis B infection and hepatocellular carcinoma. Non-compliance to the vaccination schedule, breakthrough infection and intrauterine infection are the causes of the failure. At present, we have effective measures for immunizing susceptible individuals, interrupting the routes of transmission and treating the chronically infected. The time for considering the elimination or even the eradication of HBV infection has come. This is especially true for countries where hepatitis B infection is not endemic. Nevertheless, with the admirable results achieved in the past, Taiwan should also think about elimination/eradication of hepatitis B, even though it will certainly be much more difficult than in the non-endemic countries. In exploring the possibility of eliminating/eradicating hepatitis B in Taiwan, we reviewed the epidemiology of hepatitis B, and analyzed the problems that remain to be tackled in Taiwan. We hope that Taiwan can take further steps towards the elimination or eradication of hepatitis B.     

Elimination of new chronic hepatitis B virus infections: results of the Alaska immunization program

An immunization assessment and a serologic survey were conducted to evaluate the effectiveness of a hepatitis B immunization program in eliminating hepatitis B virus (HBV) transmission among Alaska Natives in a region in which HBV infection is endemic. Hepatitis B vaccine coverage was 93% among 567 children 相似文献   

Prospects for hepatitis B virus eradication and control of hepatocellular carcinoma

Hepatitis B virus infection is the most common cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. In areas hyperendemic for HBV infection, the related complications occur mostly during adulthood. However, nearly half of all primary infection in chronic carriers occurs in the perinatal period through maternal transmission, the other half arising from horizontal transmission mainly through intrafamilial spread or injection using unsterilized needles. A universal vaccination programme is better than immunization for at-risk groups. Hepatitis B vaccination should be integrated into the Expanded Programme on Immunization in children. Universal immunization against hepatitis B virus has proved to be effective in reducing the hepatitis B carrier rate to one-tenth of the prevalence before the vaccination programme in highly endemic areas, and the incidence of hepatocellular carcinoma in children has also been shown to be significantly reduced. Continued efforts to implement universal vaccination programmes worldwide will very likely reduce the incidence of hepatitis B virus-related diseases, particularly liver cirrhosis and hepatocellular carcinoma.     

HEPATITIS B VACCINATION COVERAGE AND POSTVACCINATION SEROLOGIC TESTING AMONG MEDICAL STUDENTS AT A PUBLIC UNIVERSITY IN BRAZIL

The aim of this cross-sectional study was to determine the hepatitis B vaccination coverage among medical students at a public university in Rio de Janeiro, Brazil, and their compliance with the postvaccination serologic testing recommendations. Of the total of 858 students, 675 (78.7%) participated in the study. Among the participants, 48.9% (95% CI: 45.1% to 52.7%) were vaccinated against hepatitis B (received ≥ 3 doses of the vaccine), 31.6% were not (received 0, 1 or 2 doses), and 19.6% did not know their vaccination status. Hepatitis B vaccination coverage increased from 26.0% among first-year students to 70.6% among sixth-year students while the prevalence of unknown vaccination status decreased from 39.7% among first-year students to 2.4% among sixth-year students. The frequency of unvaccinated students ranged from 23.7% among fifth-year students to 34.4% among first-year students. Only 34.8% of the vaccinated students performed the anti-HBs testing after vaccination. Among these medical students, we found a low adherence to the hepatitis B vaccination and to the postvaccination serologic testing. A comprehensive hepatitis B immunization program should be offered to students at this medical school.     

Hepatitis D outbreak among children in a hepatitis B hyper‐endemic settlement in Greenland

Summary. Hepatitis B virus (HBV) infection is endemic in Greenland with 5–10% of the population being HBsAg‐positive (chronic carriers). Surprisingly, despite of the high prevalence of HBV infection, acute and chronic hepatitis B, liver cirrhosis and primary hepatocellular carcinoma appear much less frequently than expected. The reasons for the low frequencies are unknown, but as a consequence implementation of a childhood HBV vaccination programme, though debated for years, has never been instituted. We describe an outbreak of hepatitis D (HDV) infection among children in a hepatitis B hyper‐endemic settlement of 133 inhabitants on the west coast of Greenland. In 2006 a total of 27% of the inhabitants were HBsAg‐positive (chronic carriers) and 83% were HBcAb‐positive (previously exposed). Forty‐six percent of the HBsAg‐positive persons were below 20 years of age. On follow‐up 1 year later a total of 68% of the HBsAg‐positive persons were HDV‐IgG positive. Five children, who were HBsAg‐positive in 2006, had HDV‐seroconverted from 2006 to 2007, indicating a HDV‐super‐infection. Most of the HDV‐IgG positive children had markedly elevated liver enzymes. In the multivariate analysis, among the HBV and HDV markers, presence of HDV‐IgG was most strongly associated with elevation of liver enzymes. In conclusion, the HBV‐HDV super‐infection and presumed HDV outbreak in this settlement challenges the notion that HBV infection may not be as harmless in Greenland as previously anticipated. The findings strongly suggest that HBV vaccination should be included in the child‐immunization program in Greenland.     

Hepatitis B Vaccination: A Historical Overview with a Focus on the Italian Achievements

Vaccination is the most effective way to control and prevent acute and chronic hepatitis B, including cirrhosis and HCC, on a global scale. According to WHO recommendations, 190 countries in the world have introduced hepatitis B vaccination into their national childhood immunization programs with an excellent profile of safety, immunogenicity, and effectiveness. Following vaccination, seroprotection rates are close to 100% in healthy children and over 95% in healthy adults. Persistence of anti-HBs is related to the antibody peak achieved after vaccination. The peak is higher the longer the antibody duration is. Loss of anti-HBs does not necessarily mean loss of immunity since most vaccinated individuals retain immune memory for HBsAg and rapidly develop strong anamnestic responses when boosted. Evidence indicates that the duration of protection can persist for at least 35 years after priming. Hence, booster doses of vaccines are currently not recommended to sustain long-term immunity in healthy vaccinated individuals. In Italy, vaccination against hepatitis B is met with success. In 2020, Italy became one of the first countries in Europe to be validated for achieving the WHO regional hepatitis B control targets.     

Survey of coverage, strategy and cost of hepatitis B vaccination in rural and urban areas of China

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Hepatitis B seroprevalence in Thailand: 12 years after hepatitis B vaccine integration into the national expanded programme on immunization

OBJECTIVES: To evaluate the impact of the universal hepatitis B (HB) vaccination programme on the prevalence of hepatitis B surface antigen (HBsAg) carriers and immunity to HB virus infection among children <18 years and to determine the HB seroprevalence in the Thai population. METHODS: We enrolled people in four provinces, including Chiangrai, Udon Thani, Chonburi and Nakhon Si Thammarat to geographically represent populations in the North, Northeast, Center and South of the country respectively. Serology for HBsAg, anti-hepatitis B surface (anti-HBs), and anti-hepatitis B core (anti-HBc) was tested using ELISA commercial kits. In total, 6213 subjects aged 6 months to 60 years from the four provincial hospitals and two to three district hospitals of each participating province participated. RESULTS: Overall HBsAg, anti-HBs, and anti-HBc seropositive rates amounted to 4%, 41.6% and 26.5% respectively. Of 2887 participants aged 6 months to 18 years, 2303 were born after (group I) and 584 prior to (group II) HB vaccine integration into the expanded programme on immunization of each participating province. The HBsAg seropositive rate was 0.7% among group I children and 4.3% among group II children. The prevalence rate of anti-HBc was 2.9% in group I and 15.8% in group II. In children under 18 years, the HBsAg carrier rate was 0.98% among complete vaccinees and 1.36% among participants without vaccination. CONCLUSIONS: This finding supports the efficacy of universal HB immunization in reducing the prevalence of HB infection in Thailand which is a highly endemic country.     

Liver disease in Viet Nam: screening, surveillance, management and education: a 5-year plan and call to action

Despite a high prevalence of liver disease in Viet Nam, there has been no nationwide approach to the disease and no systematic screening of at-risk individuals. Risk factors include chronic hepatitis B (estimated prevalence of 12%), chronic hepatitis C (at least 2% prevalence), and heavy consumption of alcohol among men. This combination of factors has resulted in liver cancer being the most common cause of cancer death in Viet Nam. There is a general lack of understanding by both the general public and health-care providers about the major risk to health that liver disease represents. We report here the initial steps taken as part of a comprehensive approach to liver disease that will ultimately include nationwide education for health-care providers, health educators, and the public; expansion of nationwide screening for hepatitis B and C followed by hepatitis B virus vaccination or treatment of chronic hepatitis B and/or hepatitis C; education about alcoholic liver disease; long-term surveillance for liver cancer; reduction of infection transmission related to medical, commercial, and personal re-use of contaminated needles, syringes, sharp instruments, razors, and inadequately sterilized medical equipment; and ongoing collection and analysis of data about the prevalence of all forms of liver disease and the results of the expanded screening, vaccination, and treatment programs. We report the beginning results of our pilot hepatitis B screening program. We believe that this comprehensive nationwide approach could substantially reduce the morbidity and mortality from liver disease and greatly lessen the burden in terms of both lives lost and health-care costs.     

Prevalence of vaccine-induced escape mutants of hepatitis B virus in the adult population in China: a prospective study in 176 restaurant employees

BACKGROUND AND AIM: Hepatitis B virus (HBV) variants with mutations in the S gene would pose a substantial risk to the community as current HBV vaccines are not effective in preventing infection with them. The majority of such vaccine escape mutants so far reported have been found while studying vertical transmission of HBV; the vaccine failure rate in connection with vaccine escape mutants in adults is not clear at the moment. The purpose of this study was to evaluate the efficacy of immunization against HBV in the adult population by analysis using polymerase chain reaction (PCR) to detect HBV-DNA, and also to elucidate the type of mutation encountered in vaccine failure cases. METHOD: A total of 176 adult restaurant employees in China, who had been vaccinated according to the food epidemic law, were enrolled in a standard vaccination program. Their serum HBV-DNA was determined before and 1 year after the completion of the vaccination program. In those infected with HBV, despite having received the HBV vaccine, direct sequencing within the S gene of the amplified samples was conducted. RESULTS: Although only two cases were found to be hepatitis B surface antigen (HBsAg) positive 1 year after the completion of the vaccination program, six subjects (3.4%) were found to be HBV-DNA positive assessed by a nested PCR. Four out of these six cases had a point mutation within the 'a' determinant; they were Gly-145-Ala, and Ile/Thr-126-Asn/Ser. CONCLUSION: The HBV vaccine failure rate assessed by using PCR analysis was 3.4% (six of 176) in the Chinese adult population undergoing the HBV vaccination program. Hepatitis B virus variants with missense mutation within the 'a' determinant were responsible in most cases.     

Hepatitis A and B immunization for individuals with inherited bleeding disorders

Summary.  Hepatitis A and B vaccines are highly effective tools that can greatly reduce infection risk in the bleeding disorder population. Although hepatitis A and B immunization for individuals with bleeding disorders is universally recommended, various advisory bodies often differ with respect to many practical aspects of vaccination. To review the published literature and guidelines and form a practical, comprehensive and consistent approach to hepatitis A and B immunization for individuals with bleeding disorders. We reviewed published immunization guidelines from North American immunization advisory bodies and published statements from North American and international haemophilia advisory bodies. A search of the MEDLINE database was performed to find original published literature pertaining to hepatitis A or B immunization of patients with haemophilia or bleeding disorder patients that provided supporting or refuting evidence for advisory body guidelines. Various advisory bodies' immunization guidelines regarding individuals with bleeding disorders have contradictory statements and often did not clarify issues (e.g. post vaccination surveillance). Published literature addressing immunization in bleeding disorder patients is sparse and mostly examines route of vaccine administration, complications and corresponding antibody response. Although the risk of hepatitis A and B infection is low, the use of simple measures such as vaccination is reasonable and advocated by haemophilia advisory bodies. Following our review of the available literature and North American guidelines, we have developed comprehensive and practical recommendations addressing hepatitis A and B immunization for the bleeding disorder population that may be applicable in Bleeding Disorder clinics.     

Current hepatitis B virus infection situation in Indonesia and its genetic diversity

Indonesia has a moderate to high endemicity of hepatitis B virus(HBV) infection. The risk for chronic HBV infection is highest among those infected during infancy. Since 1997, hepatitis B(Hep B) vaccination of newborns has been fully integrated into the National Immunization Program. Al though HBV infection has been reduced by the universal newborn Hep B immunization program, it continues to occur in Indonesia. The low birth dose coverage and the presence of vaccine escape mutants might contribute to this endemicity among children. Although limited information is available for an analysis of occult HBV infection(OBI), several variations and substitutions in the pre-S/S region have been detected in Indonesian HBV strains. Additionally, persistent infection and disease progression of chronic hepatitis B are related to not only viral factors but also the host genome. Indonesia is one of the most ethnically heterogeneous nations, with Javanese and Sundanese as the two highest ethnic groups. This multi-ethnicity makes genomic research in Indonesia difficult. In this article, we focused on and reviewed the following aspects: the current hepatitis B immunization program and its efficacy, OBI, HBV infection among high-risk patients, such as hemodialysis patients, and research regarding the host genome in Indonesia.     

Hepatitis B vaccination

Alcoholics are at risk to develop hepatitis B infections, chronic active hepatitis, and even hepatoma. Hence, immunization with hepatitis B vaccine is recommended. However, immune abnormalities may coexist which alter their responsiveness to vaccination. This study compares the immune response to this vaccine in controls (group I), alcoholics without overt liver disease (group II), and alcoholics with clinical liver disease (group III). By the seventh month after the initial vaccination, 89% in group I, 70% in group II, and 18% in group III had a response >36 RIA units. The magnitude of the response was significantly different in groups I, II, and III (19,456 vs 8,326 vs 153 RIA units, respectively; P <0.05, group I vs III). In those who did not respond, a significant (P < 0.02) lower helper/inducer (T ₄)class of lymphocytes was observed as compared to patients who exhibited an adequate response. These observations suggest: (1) that the response to hepatitis B vaccine is a T-cell-dependent event and (2) that in this population, using the existing vaccine, postvaccination evaluations of antibody concentrations are needed before protection against hepatitis B infection can be assumed.This research was funded by the Veterans Administration, Cincinnati, Ohio; and Merck, Sharp and Dohme Laboratories.     

A 12-year cohort study on the efficacy of plasma-derived hepatitis B vaccine in rural newborns

AIM:To understand the anti HBs persistence and the long-term preventive efficacy in rural newborns after vaccination with plasma-derived hepatitis B vaccine.METHODS:In the time of expanded program on immunization (EPI), the newborns were vaccinated with 10&mgr;gcenter dot3 doses of hepatitis B vaccine and 762 newborns who were HBsAg negative after primary immunization were selected for cohort observation from 1986 to 1998. Their serum samples were detected qualitatively and quantitatively for hepatitis B infecting markers, including HBsAg, anti-HBs and anti-HBc by SPRIA Kits. The annual HBsAg positive conversion rate was counted by life-table method.RESULTS:(1)The anti-HBs positive rate was 94.44% for the babies born to HBsAg negative mothers and 84.21% for those born to HBsAg positive mothers in the 1st year after immunization, and dropped to 51.31% and 52.50% in the 12th year respectively.GMT value was dropped from 31.62 to 3.13 and 23.99 to 3.65 in the 2nd to the 12th year respectively. There was a marked drop in GMT at the 3rd to the 5th year, and in anti HBs positive rate at the 9th to the 10th year. (2) In the period of 12 years observation, the person-year HBsAg positive conversion rates were 0.12% (5/4150.0) in newborns born to HBsAg negative mothers and 0.20% (1/508.0) in those born to HBsAg positive mothers, and none of the HBsAg positive converted children became HBsAg chronic carriers. Compared with the baseline before immunization, the protective rates were 97.19% and 95.32% respectively.CONCLUSION:The protective efficacy of plasma-derived hepatitis B vaccine persisted at least 12 years, and a booster dose seems not necessary within at least 12 years after the primary three-doses immunization to newborns born to HBsAg negative mothers.