A universal childhood vaccination program was launched in Indonesia in 1997 and its coverage was estimated to be high (approximately 90%) on the basis of the local records for Lamongan in East Java, Indonesia. The Indonesian government provided hepatitis B vaccines produced in Indonesia to health centers called puskesmas.
Most infants, especially in rural areas, were taken to puskesmas
to be vaccinated. Plasma-derived HBV vaccine was produced in Indonesia until 1997, when it was replaced by a recombinant hepatitis B vaccine. In this study, some children had received the plasma-derived vaccine and others had received the recombinant vaccine during infancy. Although a higher loss rate of anti-HBs was detected when the recombinant vaccine was used, it may provide better protection than the plasma-derived vaccine.19
In the initial vaccination program in Indonesia, three doses of recombinant vaccine were administered, with the first dose being given within 12 hours of birth to prevent perinatal HBV transmission, and the second and third doses being given at one and six months of age, respectively, in accordance with national guidelines. However, the government now recommends the first dose of HBV vaccine to given within seven days of birth.
Presently in Indonesia, an HBV-diphtheria-pertusis-tetanus combination vaccine is given at birth, followed by a monovalent HBV vaccine. In Indonesia, recombinant hepatitis B vaccines that include pre-S1 and pre-S2 regions currently unavailable. However, this new triple-antigen vaccine is more efficient than the single-antigen vaccine,20,21
and prevents infection from vaccine-escape mutants.22
The triple-antigen vaccine should be considered in our study area where the prevalence of anti-HBs remains insufficient among children.
This study was unable to assess the actual coverage rate because no individual vaccination records remained. For this reason, efficacy of vaccination was not evaluated in this study. However, this study did show that acquiring protective antibody against HBV infection was insufficient among children born after introduction of the universal vaccination program. There are two possible explanations for this finding. First, the first dose of vaccination may have been delayed until after birth. To prevent perinatal transmission, the first dose should be given as soon as possible after birth.23
In reality, the first dose of HBV vaccine was often given several months after birth because the vaccinators and parents were fearful that the infant might have been killed by being immunized so soon after birth.5
Moreover, because giving birth at home is still common, such children have less opportunity to receive the vaccine than those born in a hospital.4
Failure to administer the vaccine in a timely manner will reduce the impact of vaccination in countries with a high prevalence of HBV infection,5
such as Indonesia. Second, loss of protective antibody against HBV infection may have occurred in some children. In previous studies in Taiwan, protective anti-HBs titers gradually decreased by age 12; a higher loss rate of anti-HBs was demonstrated in children immunized with the recombinant vaccine.24–26
This study identified seven HBsAg-positive children, and we suggest that these children were naturally infected during infancy. The prevalence of HBsAg (3.1%) in this study was similar to that among the general population in Indonesia.5
Causes of the failure to detect HBsAg in serum may include mutations in the S regions of the virus genome, which is also known as occult HBV infection.27
In this study, the R-PHA assay was used to screen for HBsAg positivity. This assay was useful but less sensitive (around 93%) than an EIA.28
In addition, accuracy of the EIA assay was higher than that of the R-PHA.29,30
Thus, we confirmed the presence of occult HBV infection by using the EIA.
We identified five HBsAg-negative children who were positive for HBV DNA and considered them to be children with occult HBV infections. The status of the five children with undetectable HBsAg was as follows: child L44 had recovered from wild-type HBV infection because of production of anti-HBs and a low viral load; child L62 had a vaccine-escape mutant; and children L29, L33, and L109 were naturally infected with vaccine-escape mutants and did not show production of anti-HBs after vaccination.31
These results suggest that potential vaccine-escape mutants exist within normally infected HBV carriers and that such carriers do not produce detectable HBsAg.
Mutations in the a
determinant region (amino acids 121–149) affect the structure of the S region and are known to cause vaccine-escape mutations during immunization. The G145R mutation is the most common vaccine-escape mutant after immunoprophylaxis and in nature.32
Another amino acid substitution, T126I, which is unique to genotype C, has also been reported to affect the antigenicity of HBsAg.33–35
T143S was invariably associated with T126I in this study, suggesting that amino acid substitutions (not T126I itself, but in combination with T143S) affect the antigenicity of HBsAg. In this study, T126I appeared in only HBV/B and was not specific to genotype C, in contrast to findings of a previous study. Because the T126I substitution involves the largest change in chemical properties, it is most likely to cause structural changes in HBsAg.33–35
In addition, A1762T/G1764A was observed in only one child, who had recovered from wild-type HBV infection. Although previous studies have reported A1762T/G1764A mutations in occult HBV infection,11–13
the correlation between these mutations and occult HBV infection remains unclear. No other mutations were found in the core region in this study.
All 10 HBV/B strains were classified into subgenotype B3 (HBV/B3), which is prevalent in Indonesia. One strain of HBV/C had high homology with HBV/C6, which was reported as a novel strain from Papua (accession no. AB493840).36,37
HBV infection in children is still endemic in East Java. We detected several variants in the a
determinant region in children who were HBsAg negative, and T126I might be one of the viral mechanisms that help the virus to escape from current hepatitis B vaccines. Emergence of viruses capable of escaping neutralization by vaccine-induced antibodies poses a serious threat to our ability to control hepatitis B.31
This pilot study indicates the presence of unique HBV among children in East Java. Because this study was small, an analysis of a larger population is necessary to confirm our findings. Empirical data are essential for future policy changes on the maintenance of the vaccination program.