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Waning immunity to plasma-derived hepatitis B vaccine and the need for boosters 15 years after neonatal vaccination
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Hepatology
Volume 40, Issue 6, December 2004
Chun-Yi Lu 1, Bor-Luen Chiang 1 2, Wei-Kuang Chi 3, Mei-Hwei Chang 1, Yen-Hsuan Ni 1, Hsu-Mei Hsu 4, Shiing-Jer Twu 4, Ih-Jen Su 4, Li-Min Huang 1 *, Chin-Yun Lee 1
1Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
2Graduate Institute of Clinical Medicine, National Taiwan University Hospital, Taipei, Taiwan
3Development Center for Biotechnology
4Center of Disease Control, Department of Health, Taipei, Taiwan
ABSTRACT
Neonatal immunization with hepatitis B (HB) vaccine is highly effective; however, more needs to be learned about the duration of protection and indications for boosters. We measured antibody to HB core antigen (anti-HBc), HB surface antigen (HBsAg), and pre- and postbooster titers of HBsAg antibody (anti-HBs) 15 years after primary neonatal immunization with plasma-derived HB vaccines in 2 cohorts of 15-year-old children.
Group A consisted of 78 children who were born to HB e antigen-positive HBsAg carrier mothers and had developed protective levels of anti-HBs antibodies (10 mIU/mL) following HB immunization. Group B consisted of 113 apparently healthy children whose anti-HBs titers after vaccination were unknown. Anti-HBs was undetectable (antibody titer <10 mIU/mL) in 29.9% in group A and 62.4% in group B (P < .001). Anti-HBc was detected in 33.3 % in group A and 4.4 % in group B (P < .001). After a single booster dose of HB vaccine, 2.7% in group A and 3.3% in group B remained anti-HBs-negative. A blunted serological response was noted in approximately 20% in both groups. One HBsAg carrier was detected in group A (1.3%) and 4 in group B (3.5%).
Fifteen years after neonatal immunization with plasma-derived HB vaccine, a large proportion of children exhibited waning immunity. This poses the risk of breakthrough infection. A single booster augmented the serological response to the vaccine in most but not all subjects. In conclusion, our findings suggest that one or more booster immunizations are needed in seronegative subjects by at least 15 years following neonatal immunization with plasma-derived HB vaccine.
Article Text
Although substantial progress has been made in preventing hepatitis B (HB) infection and its complications through the use of HB vaccines, there are still 400 to 500 million HB carriers worldwide. The large number of HB carriers presents a major threat to new generations. Thus worldwide access to HB immunization and appropriate use of HB vaccines continues to be critical to further reduce the burden of this disease.
HB vaccines became available in the early 1980s. They are highly immunogenic and efficacious. Most vaccines induce protective antibody against HB surface antigen (anti-HBs) after a primary series of immunizations. This is followed by a gradual decline in titer. Vaccinees who have low or undetectable anti-HBs antibodies are reported to exhibit a robust anamnestic response up to 10 years after primary immunization. Currently no vaccinee has become a carrier 5 to 10 years after primary immunization; thus many investigators consider boosters to be unnecessary at 10 years of age. In 2000, the European Consensus Group on Hepatitis B Immunity went one step further. They issued a statement recommending against the use of boosters of HB vaccine in immunocompetent individuals 15 years after primary immunization. Some investigators continue to recommend boosters because of the progressive decline of anti-HBs over time and the associated potential risk of development of HB infections.
Children born to mothers positive for HB surface antigen (HBsAg) and HB e antigen (HBeAg) are at a high risk of vertical transmission of HB virus (HBV). Their siblings and other family members are also more likely to be positive for HB through vertical and/or horizontal spread of HBV. There is also an increased risk of spread of HBV through sexual contact as the children mature. For these reasons, it is important to determine the need for a booster dose of HB vaccine in this high-risk group.
In this report, we describe the seromarkers and immune response to HBV before and after booster injections in two cohorts of children born during the nationwide HB vaccination program begun in Taiwan in 1984. One cohort consisted of high-risk children born to HBeAg-positive and HBsAg-positive mothers. The other cohort consisted of apparently healthy children representative of the general population. All of the children had received 4 doses of plasma-derived HB vaccine 15 years prior to follow-up. We provide evidence of waning immunity in a substantial proportion of these cohorts. In addition, we report several breakthrough HB infections, including one in an individual proven to be positive for anti-HBs after vaccination. We also note a high risk for acquisition of the antibody against HB core antigen (anti-HBc), and a blunted response to one or two boosters in some subjects.
AUTHOR DISCUSSION
HB vaccination programs are highly effective and have led to marked declines in carrier rates and the incidence of hepatocellular carcinoma in countries such as Taiwan that are highly endemic for HBV. However, our results clearly show that natural exposures to HBV continued in the general population. Without reliable long-term immunity, HBV infection is unlikely to be eradicated. The current priority is to continue to protect vaccinated children who are exposed to HBV carriers in the household and community. To accomplish this, we must determine how long immunity persists, whether boosters are needed, and, if so, when and in whom they should be administered.
In a prior study of infants who had received recombinant HB vaccine in early infancy, we demonstrated that in anti-HBs-seronegative subjects at 10 years of age, one booster dose of HB vaccine induced a 100% anti-HBs seroconversion. Antibody titers rose to no less than 1,000 mIU/mL with a 900-fold increase in geometric mean titer. In the current study, we found unacceptably high rates of undetectable anti-HBs among children who had received 4 doses of plasma-derived HB vaccine as the neonatal immunization 15 years previously. Four (3.1%) of 128 children with anti-HBs levels of 100 mIU/mL or less did not respond to a HB booster vaccine. The increase of anti-HBs titers after booster at 15 years of age was often blunted, especially for children with low anti-HBs titers after the neonatal vaccination. These low responders tend to have low anti-HBs titers and respond inadequately to booster vaccinations at the age of 15, and hence carry the greatest risks of getting breakthrough HB infections.
The most alarming finding, however, was the detection of 1 HBsAg carrier among 78 children (1.3%) who had responded to the neonatal immunization. The child remained seronegative until age 7. At the age of 15, he was proved to have 2 different genotypes of HBV, though only 1 of them was similar to his mother's. Therefore, horizontal infections from one or more sources accounted for the seroconversion that happened between 7 and 15 years of age. Besides, no glycine 145 arginine mutation was detected in the HB surface protein of the child. Breakthrough infection due to waning and eventual loss of the vaccine protectiveness - rather than infection by escaped mutants - is likely.
Children living in a household with HB carriers are more likely to receive a natural booster for HBV. We found that children born to mothers who were doubly positive for HBsAg and HBeAg were much more likely to exhibit anti-HBc, a marker of a natural booster effect, than nonselected children representative of the general population. However, both groups continued to have high rates of undetectable antibody 15 years after primary immunization. In previous studies, we found that in Taiwanese children born to mothers who were doubly positive for HBsAg and HBeAg, the anti-HBc-positive rates at 5 and 10 years were 12%. In the current study, the rate was 33.3% at 15 years of age. Although these data were derived from different cohorts, the risk of HB infection appears to rise between 10 and 15 years. The reasons for this phenomenon are not clear, but they may be related to the intimate mother-child interaction during the first 5 years of life and changes in lifestyle and sexual activity in older children.
Another concern is that batch-to-batch variation in immunogenicity might present in plasma-derived HB vaccines. Positive anti-HBs rates in neonates using plasma-derived HB vaccine have been reported to be as low as 75%. Even if the children acquired protective antibodies after the vaccination, the antibody titers might be low. In the present study, 41% of children in group A had anti-HBs titers less than 100 mIU/mL. Without evidence of technical problems in vaccination or antibody determination, suboptimal batches of vaccine were more likely to be blamed for the high proportion of children with low anti-HBs titers at 18 months of age. Especially for children with low initial anti-HBs titers, the duration of protection against HB infection remained uncertain. Our results suggest that immune memory was well preserved in most of the children even though waning of anti-HBs was significant. However, for children who had a low response to HB vaccine initially, breakthrough infections might occur 10 to 15 years later.
Based on our previous and current observations, it seems reasonable to determine the anti-HBs status of children at 10 to 15 years after receiving plasma-derived HB vaccine and provide a booster to those whose immunity has waned. Similar considerations should be given to children who received recombinant vaccine. Alternatively, poor responders after the neonatal vaccinations should be identified, and additional doses of vaccine should be provided early on.
Subjects.
Two groups of children were recruited. Group A consisted of 78 15-year-old adolescents (40 male and 38 female) who were born to HBeAg-positive and HBsAg-positive mothers. They were documented to have received 4 doses of plasma-derived (5 g/dose) HB vaccine (Hevac B; Pasteur, Paris, France) at 0, 1, 2, and 12 months during 1988. All of them also received 0.5 mL (145 IU) of hepatitis B immunoglobulin (Hyper-Hep, Miles, PA) within 24 hours after birth. All were shown to be negative for HBsAg and positive for anti-HBs at the age of 18 months. Group B included 113 15-year-old volunteer students (57 male and 56 female) who had completed 4 doses of plasma-derived HB vaccination (Hevac B; Pasteur) during infancy. Their serological status against HBV prior to the study was unknown.
After obtaining informed consent, all children underwent blood tests for HBsAg, anti-HBs, and anti-HBc. A booster dose of 20 g of a recombinant DNA HB vaccine (Engerix-B; SmithKline Beecham, Rixensart, Belgium) was given to all subjects in group A and 63 children in group B who were HBsAg-negative and whose anti-HBs titer was less than 100 mIU/mL. Another blood sample was taken 4 weeks after booster vaccination.
Subjects in group B were offered a second dose of booster if they remained anti-HBs-seronegative 4 weeks after the first dose of HBV vaccine booster. A third blood sample was taken 4 weeks later in this subgroup.
HB Markers.
Radioimmunoassays (Ausab, Ausria II, and Corab; Abbott Laboratories, North Chicago, IL) were used to assay anti-HBs, HBsAg, and anti-HBc. Anti-HBs concentrations greater than 10 mIU/mL were considered protective. Concentrations between 10 and 100 mIU/mL were considered low titers. A carrier was defined as an individual who was HBsAg-positive for more than 6 months.
Genotyping for Hepatitis B Virus.
Genotype analysis for HBV was conducted by both restriction fragment length polymorphism analysis and direct sequencing of products of nested polymerase chain reaction using type-specific primers targeting pre-S/S region.
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