Twenty-two years follow-up of a prospective randomized trial of hepatitis B vaccines without booster dose in children: Final report

Abstract

Long-term immunogenicity and efficacy of HBV vaccination with different regimens of HBV vaccines (A: 2-dose recombinant vs. B: 3-dose recombinant vs. C: 3-dose plasma-derived vaccines) without booster dose were examined in 318 Chinese children. Geometric mean titer (GMTs) of anti-HBs of group A subjects was significantly lower than that of groups B and C subjects at years 1, 5, 10 and 15. At year 22, the proportion of subjects with anti-HBs ≥10 mIU/mL for groups A, B and C were 35.3%, 76.5% and 52.4%, respectively (p < 0.05 between groups A and B) in 55 subjects. In the 22 years study period, none was found to be HBsAg positive, and 72 subjects had ≥1 episodes of anamnestic response. In conclusion, the 3-dose regimens have a better long-term immunogenicity. In terms of protection against HBV infection, the 2-dose and 3-dose vaccines had equal efficacies.

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.