Hepatitis A and B vaccination and public health

Summary.  The introduction and implementation of hepatitis B vaccination programmes in areas of high endemicity has been very stressful. However, this initial accomplishment has led to the reassessment of priorities in some countries which could undermine these early successes. Work still remains to be done to support and implement interventions that will bring us closer to the WHO goal and to the control of hepatitis B in the community at large. Hepatitis A vaccine strategy for immunizing toddlers is shifting to those countries with intermediate endemicity where increasing morbidity in adults is being observed. Accumulating evidence indicates that such programmes can result in impressive reductions in the incidence of hepatitis A by herd immunity. Monitoring of these populations to determine durability of protection will be important to avoid shifting the infection to the older age population, when symptoms are more likely to occur. National policies need to consider hepatitis A vaccination in the context of other public health priorities.     

Hepatitis B surface antigenaemia following vaccination with a combined vaccine against hepatitis A and B

Summary.  We report a case of transient hepatitis B surface antigenaemia (HBsAg) following vaccination with a combined vaccine against hepatitis A and B in healthy adults. This phenomenon has been observed following administration of recombinant hepatitis B (monovalent) vaccine, mainly in newborns or dialysis patients. Reports on healthy adults are much less frequent and mostly concern blood donors. The frequency of its occurrence is largely unknown but its duration does not exceed 28 days. It is not detected by all available assays. It is caused by a passive tranfer of antigen by vaccination, and not by viral replication; hence there is no risk for vaccination-induced infection. An important implication resulting from our findings is that the results of HBsAg assays should be interpreted according to the time elapsed since the last administration of a recombinant monovalent vaccine against hepatitis B or a combined vaccine against hepatitis A and B.     

Hepatitis B virus vaccination and antenatal transmission of HBV markers to neonates

The high prevalence of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in pregnant women is considered to be the most important factor contributing to the high carrier rate of HBsAg in some populations. Several factors, including the age at which infection occurs, predispose to the acquisition and frequency of the carrier state. The proportion of infected people who become chronic carriers ranges from about 80 to 95% for babies born to HBsAg/HBeAg-positive mothers. In this study of Indonesian infants receiving only active immunization against HBV, we measured the HBV markers passively acquired from their HBsAg-positive mothers. The relationship of these markers with vaccination response and with HBV infection status was studied longitudinally in the infants. In the exposed neonates from the HBsAg-positive mothers (n=61), the seroconversion rate to hepatitis B surface antibody (HBsAb) positivity was 95% after the first booster vaccination, with a geometric mean titre (GMT) of 2017 IUl-1. After 60 months, the GMT in this group decreased to 50 IUl-1. Four newborns in this group became HBsAg carriers. Of the four vaccination failures, three newborns were HBsAg/HBeAg positive at birth, suggesting that they had been infected in utero. No vaccination strategy (active alone, or passive/active) can prevent this transmission from occurring. One carrier was HBsAg negative at birth and up to month 4 but was HBsAg positive at month 12 and subsequently, suggesting a postnatal infection. Vaccination early in life can, to a large extent, prevent perinatal transmission and hepatitis B virus (HBV) infection later in infancy and childhood. In this study, the protective efficacy of the vaccination was 85% in the subcohort of neonates from HBeAg-positive mothers and 100% in the subcohort of neonates from HBeAg-negative mothers. Lack of maternal antibodies to hepatitis B core antigen (HBcAb) correlated strongly with transmission of HBV infection.     

Immune response after hepatitis A vaccination in haemodialysis patients: Comparison with hepatitis B vaccination

This study evaluates the immune response of 20 haemodialysis (HD) patients vaccinated with hepatitis A (HA) vaccine and eight patients vaccinated with hepatitis B (HB) vaccine. Twenty patients and 22 healthy adults were immunized three times (months 0, 1 and 6) intramuscularly with a 0.5 μg dose. All members of both groups were positive for the antibody to hepatitis A virus (anti-HAV) after three vaccinations. The geometric mean titres at 7 months were similar in both groups. No serious side effects were observed. Eight of the HD patients with HA vaccination were injected with yeast-derived hepatitis B vaccine. The three doses of 10 μg were administered intramuscularly at 0, 1 and 6 months. The occurrence of antibody to hepatitis B surface antigen (anti-HBs) was late in HD patients and the anti-HBs level in HD patients was lower than that in healthy subjects. These results indicate that this HA vaccine has good immunogenicity compared with the HB vaccine and that the standard three doses of HA vaccine given at 0, 1 and 6 months are safe and effective even in HD patients.     

Hepatitis A and B in Australian Aboriginals living in an urban community

A high prevalence of hepatitis B virus (HBV) infection is recognized in Australian Aboriginals, but epidemiological data on contemporary Aboriginal communities are limited. This study investigated HBV infection in urban Aboriginals from Condobolin, New South Wales, Australia. Sera from 236 Aboriginals and 125 Caucasians were screened by radio-immunoassay for hepatitis B surface and e antigens, antibodies to surface, e and core antigens (including IgM anti-HB core—EIA), and antibodies to hepatitis A virus (anti-HAV). Sera which were positive for HBsAg were tested for hepatitis B e antigen, HBV-DNA polymerase and HBV-DNA molecular hybridization. More than half the Aboriginals tested (57.6%) had serological evidence of HBV infection (16.9% HBsAg) and 84.5% had anti-HAV. There were no statistically significant differences between males and females for any marker. The Caucasians had 7.2% HBV antibodies, no HBsAg and 32.0% anti-HAV. Aboriginal children in their first decade had 36.0% HBsAg and the prevalence of this antigen fell to 4.2% in Aboriginals over 50 years of age. The opposite age trend was found for antibodies which increased from 16% in children to a peak of 55.2% for adults aged 30–39. Endemic hepatitis B acquired early in life is evident in this Australian Aboriginal urban community. Transmission may be vertical or horizontal or both. Immunoprophylaxis with immune globulin and hepatitis B vaccine is recommended for neonates and seronegative individuals. The 91% prevalence of anti-HAV in these Aboriginals aged 10–19 years is comparable to that of the developing world.     

Therapeutic vaccination in chronic hepatitis B

AIMS: The aim was to test the efficacy of a pre-S2-containing vaccine (Genhevac-B) in chronic hepatitis B (CHB). Twenty-five naive patients (22 male, three female; median age 35; range: 6-69 years) with CHB were recruited. The inclusion criteria were: hepatitis B e antigen (HBeAg) positive or HBV-DNA detectable with liquid hybridization; alanine aminotransferase (ALT) is at least 1.5-fold the upper normal limit and histological evidence of chronic hepatitis. METHODS: In the first period, all patients received monthly injections of 20, 40 and 60 microg of the vaccine. One month after the last injection, patients who still had HBV-DNA were divided into two randomly assigned groups. While the patients in the first group and the patients who lost HBV-DNA in the first period continued to receive monthly injections of 20 microg vaccine for a further 6 months, the patients in the second group received 9 MU interferon alpha-2b (Roferon-A), three times per week using the same method as for the first group. Patients were followed up after 12 months without treatment. Response was defined as the loss of HBV-DNA and normalization of ALT. RESULTS: Six of the 25 patients lost HBV-DNA after 3 months. Nine of the remainder were randomly placed in the first group (vaccine-only) and 10 were placed in the second group (vaccine + interferon). End-of-treatment response was achieved, overall, 8/15 from the vaccine group and 6/10 from the combination. One patient from each group relapsed during the follow up. Overall, the sustained response (SR) rate was 46% (7/15) in the vaccine group, and 50% (5/10) in the combination group. Histological improvement was achieved in 6/7 SR with vaccine-only and all five with combination treatment, while 1/8 of failures of vaccine and 2/5 of failures of combination improved. CONCLUSIONS: It was concluded that Genhevac-B decreases serum HBV-DNA levels in the majority of patients with CHB and sustained clearance was achieved in some patients. Combination of interferon-alpha with Genhevac-B is effective for the vaccine failures and may increase sustained response compared to interferon-alpha alone. However, the mechanism of action is yet to be explained.     

我国乙型肝炎疫苗研究及接种的新进展

乙型肝炎病毒(Hepatitis B virus,HBV)引起的相关疾病仍然是困扰医疗界的一大难题,全球每年有(100～150)万人死于与HBV相关的疾病,尤其以慢性乙型肝炎者尚无有效的治疗方法,这使得接种乙型肝炎疫苗成为了目前防治乙型肝炎的最经济和有效的手段,乙型肝炎疫苗研究也因此有了长足发展。本文对乙型肝炎疫苗的现状及研究进展进行了整理,以提高临床医师对乙型肝炎疫苗的认识。     

Long-term follow-up of hepatitis B vaccination in susceptible hospital personnel

Two hundred and sixty-seven susceptible hospital personnel who had been randomly divided into three groups to receive different doses (5 micrograms, 2 micrograms or 1 microgram) of a plasma-derived hepatitis B vaccine on a four-dose schedule were investigated annually for 4 years. Of them, 251 were vaccine responders. The percentages of persistence of antibody to hepatitis B surface antigen (anti-HBs) in these 3 groups were 95.5% (84/88), 92.3% (72/78) and 95.3% (81/85), respectively (P greater than 0.05). During the follow-up period, 12 of 21 (57.1%) responders with low anti-HBs titres (10-100 miu/mL) and 3 of 48 (6.3%) responders with medium anti-HBs titres (101-1000 miu/mL) were found to be anti-HBs seronegative, while none of the 182 candidates with high anti-HBs levels (greater than 1000 miu/mL) lost their anti-HBs. The 4 year cumulative rate of natural booster in the responders was 11.6% (29/251). None of the candidates became HBsAg positive during the follow-up period. This study revealed that low dose hepatitis B vaccine can provide satisfactory immunogenic response and long-term efficacy in Chinese adults and that the persistence of immunogenicity is not related to the vaccine dose but to the candidate's own initial anti-HBs response.     

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.     

B Cell-mediated Humoral Immunity in Chronic Hepatitis B Infection

B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.     

Hepatitis B Virus-Associated Hepatocellular Carcinoma

Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.     

辅助性T细胞表位HBV表面抗原融合基因真核表达质粒的构建

为提高HBVDNA疫苗的免疫效率，将一个通用型辅助性T细胞表位基因引入HBV表面抗原基因的5‘末端，构建成真核表达质粒。PCR方法合成PADRE-HBsAg目的基因，产物与pMDl8T载体连接，经Hind Ⅲ，EcoR Ⅰ双酶切，再克隆入真核表达载体pcDNA3．1( )。酶切及测序鉴定，该真核表达载体构建成功，为进一步观察其特异性细胞和体液免疫反应奠定了基础。     

Hepatitis B vaccination of 113 hemophiliacs: lower antibody response in anti-LAV/HTLV-III-positive patients

One-hundred thirteen adults and children with hemophilia or other congenital bleeding disorders were vaccinated against the hepatitis B virus. Each patient was given three subcutaneous injections of the vaccine at monthly intervals and then a fourth booster dose 14 months after the first. The vaccine was highly immunogenic, since 111 of 113 patients (98%) produced anti-HBs (10 mIU/ml or more). After the first three vaccine doses and after the booster dose, ten anti-LAV/HTLV-III-positive hemophiliacs produced anti-HBs but had a lower average titer than anti-LAV/HTLV-III-negative hemophiliacs. Of the 23 patients treated with concentrates in the 15 month postvaccination period only, none acquired HBV infection. Of the 50 patients treated with concentrates also in the 6 month prevaccination period, one developed hepatitis B. In summary, the vaccine was highly immunogenic in both children and adults with hemophilia; anti-LAV/HTLV-III-positive patients responded to the vaccine, but the average anti-HBs response was lower; no case of hepatitis B occurred in patients treated with concentrates only in the postvaccination period.     

Production of antibody to hepatitis A virus and hepatitis B surface antigen measured after combined hepatitis A/ hepatitis B vaccination in 242 adult volunteers

Two batches of a new hepatitis A/hepatitis B combined vaccine were tested in 242 healthy students. Three injections, given at 0, 1 and 6 months, produced seroconversion rates and hepatitis A virus (HAV) and hepatitis B surface antigen (HBsAg) antibody levels comparable to those reported after administration of separate monocomponent vaccines. The vaccine proved to be safe and well-tolerated. Influence of host factors, such as elevated body mass index or gender, were investigated and proven to be of little influence on the immunoresponse.     

Hepatitis B vaccination alone is not adequate for the categorizing of adult subjects with isolated anti-HBc

Abstract To evaluate the meaning of isolated antibody to hepatitis B core antigen (anti-HBc), 88 Chinese subjects with isolated anti-HBc received rescreening of hepatitis B virus (HBV) markers. Eighty (90.9%) of them were still positive for this antibody and 29 were also found to be positive for antibody to hepatitis B surface antigen (anti-HBs). The remaining 51 subjects (58.0%) were positive for anti-HBc alone; 50 of them received a four-dose schedule of hepatitis B (HB) vaccine. After the initial dose, only one vaccinee disclosed an amnestic anti-HBs response, that is, anti-HBs titre > 1000 miu/mL. Forty-five vaccinees completed the vaccination schedule and 44 (97.8%) had anti-HBs response. The anti-HBs responses in 25 of these vaccinees were compared with 25 age- and sex-matched normal susceptible vaccinees. The anti-HBs response rates in both groups were the same (96 vs 96%). However, the geometric mean titre was significantly lower in the vaccinees with isolated anti-HBc (512 mIU/mL vs 4688 mIU/mL, P < 0.001). Prevaccinated sera were available in 49 vaccinees with isolated anti-HBc for detection of antibody to hepatitis B e antigen (anti-HBe) and HBV DNA; 37 (75.5%) of them had one or two of these markers. As we regarded the rescreening of HBV markers, response to hepatitis B vaccination and presence or absence of anti-HBe and/or HBV DNA together for categorizing the 88 subjects with isolated anti-HBc, at least three-quarters of them had past infection of HBV. The subjects with false positive anti-HBc test were a minor group. We concluded that the presence or absence of amnestic anti-HBs response to HB vaccination is not a reliable indicator for categorizing subjects with isolated anti-HBc. Rescreening of HBV markers, with addition of anti-HBe and HBV DNA, may be helpful in determining the necessity of HB vaccination.     

Hepatitis B vaccination after living donor liver transplantation.

BACKGROUND: The efficacy of hepatitis B vaccination after living donor liver transplantation (LDLT) in patients transplanted anti-HBc-positive grafts or in patients who underwent LDLT for fulminant hepatitis B remains unknown. METHOD: A total of 11 recipients who underwent LDLT between October 1996 and October 2002 prospectively received hepatitis B vaccination three times within 6 months, starting a few weeks after the cessation of hepatitis B immunoglobulin (HBIG) prophylaxis. Serial quantification of the hepatitis B surface antibody (HBsAb) was performed. RESULTS: At the last follow-up, six out of 11 patients (54.5%) had seroconversion and were free from HBIG thereafter. Four out of those six responders had a peak HBsAb level of more than 1000 IU/L, while the other two patients had peak HbsAb levels below 1000 IU/L. Five patients never responded to the treatment and were back to HBIG prophylaxis. The average age of the six responders was 25.5 years, which was significantly younger than that of non-responders (44.4 years, P<0.05). None had side effects or hepatitis B infection during the study period. CONCLUSIONS: In conclusion, the use of this treatment modality could be used to reduce the cost of HBIG.