Twenty-two years follow-up of a prospective randomized trial of hepatitis B vaccines without booster dose in children: Final report
Introduction
The chronicity of hepatitis B virus (HBV) infection primarily depends on the age of acquiring the HBV. HBV infection in early life, when the immune system is immature, is more likely to result in chronic hepatitis B infection than infection in adulthood when the immune system is fully developed [1]. In endemic areas such as Asia, which contribute more than 75% of the chronic hepatitis B (CHB) population, reduction of perinatal transmission and horizontal transmission in early childhood are of utmost importance. Neonates born to hepatitis B surface antigen (HBsAg) positive mothers have high chance of acquiring the infection in the perinatal period. The transmission risk can be as high as 70–90% when the mother is hepatitis B e antigen (HBeAg) positive. In utero transmission, though possible, is believed to be rare (less than 2%) [2]. When HBV vaccine and hepatitis B immunoglobulin are given within 12–24 h after birth, it is 90% effective in preventing acute and chronic HBV infection in infants with HBeAg-positive mothers. In 1990, the World Health Organization (WHO) recommended the integration of HBV vaccine in all national immunization programs. In Taiwan, it has been shown that the implementation of universal HBV vaccine results in the reduction of the HBV seroprevalence and most importantly the reduction of HCC incidence in children [3], [4].
HBV vaccination currently consists of 3 doses of vaccine. The protective efficacy of the vaccine is well established. Studies have shown that antibodies against HBsAg (anti-HBs) can be sustained for more than 10–15 years after primary HBV vaccination. Even when the antibody level falls to low or even undetectable level after the primary vaccination, when re-exposed to HBV vaccine challenge, a rapid reappearance of anti-HBs of high titers is observed [5]. This anamnestic response is supported by many long-term HBV vaccination studies showing that breakthrough HBV infection and chronic carriage are rarely observed in the vaccine recipients. Routine HBV booster use in immunocompetent subjects is not recommended [6], [7], [8]. Boosters were reserved for high-risk subjects like health care workers, and subjects with compromised immunity such as hemodialysis and renal transplant patients, leukemia patients and chronic hepatitis C patients. Recently, some clinical studies even suggest comparable protective efficacies noted up to 7 years between 2-dose and 3-dose regimens of HBV vaccines [9]. However, despite the persistence of anti-HBs in long-term studies, the titers of anti-HBs decrease with time. The proportion of vaccine recipients having protective level of antibodies also decreases. Although the number of vaccine recipients having breakthrough HBV infection is limited, in one study the risk factors for breakthrough HBV infection were the duration after primary vaccination and undetectable anti-HBs titers [10]. There is also concern that breakthrough infections, though not common in early years after HBV vaccine, may occur with longer follow-up.
We have reported an 18-year follow-up of a prospective randomized study on the use of HBV vaccine in children without booster doses. The aim of the present study was to make a final report examining the immunogenicity and efficacy of HBV vaccines of this cohort of subjects after 22 years of follow-up.
Section snippets
Subjects and methods
During the period between November 1984 and February 1986, children aged 3 months to 11 years old from HBV families were screened and invited for this HBV vaccination study. HBsAg, anti-HBs and antibody to hepatitis B core antigen (anti-HBc) measured by radioimmunoassays (AUS-RIA II, AUSAB, and COBAS, respectively; Abbott Laboratories, North Chicago, IL.) and alanine transaminase (ALT) were checked. Subjects were given HBV vaccines if they were negative for all HBV serologic markers (HBsAg,
Results
A total of 318 subjects with the mean age of 5.4 years were randomized to 1 of the 3 HBV vaccine regimens (105 in group A; 106 in group B and 107 in group C) after initial screening (Table 1). At 8 months, 11 subjects had anti-HBs titer less than 10 mIU/mL (6 in group A, 2 in group B and 3 in group C) and were excluded from subsequent analysis. There were no statistically significant differences among the 3 groups in the percentages of subjects who did not have anti-HBs ≥10 mIU/mL at 8 months (p =
Discussion
To our knowledge, this is the longest prospective follow-up of HBV vaccination in children. The subjects in the study represented a high-risk population because they were family members of HBV carriers, and Hong Kong is a highly endemic area for HBV infection. Any ideal vaccine should be safe and cheap that requiring only a single course of vaccination while offering life long protection from the infection. This is most important in endemic Asian and African countries where healthcare cost and
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