Abstract
Objective. Hepatitis B vaccines are usually administered on a schedule of 0, 1 to 2, and 6 months. Longer intervals between the second and third doses have been studied, but the effectiveness of hepatitis B vaccine administered at intervals of >2 months between the first and second doses have not been studied. Our objective was to compare the antibody response in recipients of Engerix-B hepatitis B vaccine administered at 12-month intervals to the response to vaccine administered at 0-, 1-, and 6-month intervals.
Methods. A total of 389 children, 5 through 16 years of age, were randomized to receive Engerix-B (10 mg) at a schedule of either 0-, 1-, and 6-month intervals or 0-, 12-, and 24-month intervals. Blood was drawn before and 1 month after the third dose.
Results. Immediately before the third dose of vaccine, 92.3% of children who received vaccine on the 0-, 1-, and 6-month schedule and 88.8% of children who received the 0-, 12-, and 24-month schedule had antibody to hepatitis B surface (anti-HBs) antigen concentrations ≥10 mIU/mL. Of the children in the 0-, 1-, and 6-month schedule, 95% received the third dose according to protocol versus 90% of those in the 0-, 12-, 24-month schedule. The geometric mean anti-HBs concentration just before the third dose for recipients of the 0-, 1-, and 6-month schedule (117.9 mIU/mL) was somewhat lower than that for the children who had received vaccine on the 0-, 12-, and 24-month schedule (162.1 mIU/mL). One month after the third dose, >98% of all children had anti-HBs concentrations ≥10 mIU/mL and high geometric mean antibody concentrations were observed in both groups: 5687 mIU/mL for children on the 0-, 1-, and 6-month schedule and 3159 mIU/mL for children on the 0-, 12-, and 24-month schedule. Body mass index was correlated inversely with final antibody concentration, but age was not a factor after adjustment for body mass index.
Discussion. Engerix-B administered on a 0-, 12-, and 24-month schedule is highly immunogenic. Providers should consider this alternate immunization schedule for children who are at low risk of immediate exposure to hepatitis B infections. vaccine, hepatitis B, hepatitis B vaccine, antigen, dose, schedule, immunization, adolescent.
- GMC =
- geometric mean concentration(s) •
- anti-HBs =
- antibody to hepatitis B surface antigen •
- BMI =
- body mass index
Hepatitis B virus vaccines provide highly effective protection against acute and chronic hepatitis B infection and the chronic carrier state.1 ,2 Immunization with hepatitis B vaccine for infants, children, adolescents, and high-risk adults is recommended by the American Academy of Pediatrics and the US Public Health Service Advisory Committee on Immunization Practices.3 ,4 Hepatitis B vaccine is administered as part of the primary infant immunization schedule at birth, 1 to 2, and 6 to 18 months or at 2, 4, and 6 to 18 months.5 The recommended immunization schedule for older children and adolescents is 3 doses with the second and third doses administered 1 and 4 to 6 months after the first dose. Because children 5 years of age and older are usually only seen on an annual basis for well-child care, the recommended schedule requires two extra physician visits. If hepatitis B vaccine could be administered at 1-year intervals, no extra physician visits would be necessary.
A variety of immunization schedules have been shown to be very effective in inducing high levels of immunity in infants and young children.1 ,3 ,4 Increasing the interval between the second and third dose from 2 to up to 11 months has resulted in higher final geometric mean concentrations (GMC) of antibody to hepatitis B surface antigen (anti-HBs) after the third dose.6 ,7 Because intervals >2 months between the first two doses have not been evaluated and immunization at annual well-child visits would be convenient, we compared the response to HB vaccine at 12-month intervals with the standard 0-, 1-, and 6-month schedule.
METHODS
Study Design
This was a prospective, open-label randomized trial.
Study Population
Healthy children and adolescents, 5 through 16 years of age, attending two pediatric practices were enrolled. Children with the following conditions were excluded 1) known previous infection with hepatitis B, 2) underlying immunosuppressive disorder or current receipt of immunosuppressive drugs (including steroids), 3) previous immunization with hepatitis B vaccine, 4) febrile illness (temperature >38°C) at time of visit, 5) families planning to move out of the study area within the 2-year study period, and 6) other known contraindications to HB vaccine. Written informed consent was obtained from parents of all children, and verbal consent was obtained from the children. This study was approved by the Joint Committee on Clinical Investigation of the Johns Hopkins University School of Medicine.
Baseline Studies
A brief questionnaire was administered to identify risk factors for hepatitis B infections in the family. The child's height and weight were obtained at the time of enrollment and at the time of the third dose of vaccine to determine body mass index (BMI). BMI was calculated from weight in kilograms divided by the square of height in meters.8 In the analyses, the mean BMI from the two measurements in the analyses was used. Age was rendered a dichotomous variable, coded 1 for >11 years old (approximately the median), code 0 otherwise.
Immunization Schedule and Randomization
Participants were randomized to receive hepatitis B vaccine at intervals of 0-, 1-, and 6-month intervals or 0-, 12-, and 24-month intervals. After consent was obtained, sealed envelopes containing the vaccine schedule were opened to determine which schedule would be used. Children were block randomized using random block sizes of 14 and 20 at each site to ensure an equal distribution to both groups. Participants were given a gift certificate when they came in for the blood draw 1 month after the third dose of vaccine to compensate for the time, inconvenience, and discomfort of the extra visit.
Vaccine
Engerix-B vaccine (10 μ, the licenced dose for 5- to 16-year-old children; hepatitis B vaccine, recombinant, SmithKline Beecham Pharmaceuticals, Philadelphia, PA) was administered intramuscularly in the left deltoid by a nurse using a 23-gauge needle.
Antibody Testing
Venipuncture blood samples were obtained at the time the third dose of vaccine was administered and 1 month later. Serum specimens were tested at the Centers for Disease Control and Prevention for anti-HBs by enzyme immunoassay (AUSUB EIA; Abbott Laboratories, Abbott Park, IL). Anti-HBs concentrations were expressed in milli-IU per milliliter.1 The serum specimen obtained at the last study visit was tested for antibody to hepatitis B core antigen to determine whether any children had contracted hepatitis B infection.
Adverse Reaction Monitoring
The child and parent(s) were asked to call the nurse or physician if any reactions other than a sore arm occurred. At the next study visit, the child and parent(s) were asked about hypersensitivity reactions.
Sample Size
The 0-, 1-, and 6-month vaccine schedule is known to induce protective levels of anti-HBs (≥10 mIU/mL) in ∼95% of normal vaccines.1 ,2 A sample size of 159 children per group was required to detect a difference of 10% in serologic response rates between the two groups with 80% power and 5% type I error. Allowing for loss to follow-up or refusal of final blood drawing, a target of 191 children per group was set.
Data Analysis
Proportions were compared with Fisher's exact test, andt tests were used to analyze the GMCs of antibody before and after the third dose of vaccine. Linear regression analyses on log-transformed anti-HBs concentrations were used to examine the relationship of physical and demographic variables to serologic response. Local smoothing, which consists of taking a moving, weighted average of the values, was used to produce the graph in Fig 2. Analyses were performed with SAS 6.11 (SAS Institute, Inc, Cary, NC) and Stata 5.0 (Stata Corporation, College Station, TX) software.
Anti-HBs concentration 1 month after third dose by mean BMI (P = .0002 for linear trend). The solid line represents a locally smoothed mean concentration.
RESULTS
Of the 389 children enrolled and randomized, a higher percentage of children in the 0-, 1-, and 6-month schedule group completed the study as defined by receipt of all study immunizations and provision of two blood specimens (Table 1). Those children who completed and those children who did not differed with respect to initial BMI (18.8 and 21.1, respectively; P= .006) and race (89% of white children completed the study, 64% of the children of other races did not; P = .002). The most common reasons given for noncompletion were moving from the study area (17 [38%]) and not obtaining first or second serum specimens (17 [36%]). At least 2 children in the 0-, 12-, and 24-month schedule group received a third dose of vaccine by a nonstudy provider. None of the children had a serious adverse reaction to the vaccine, and no unusual reactions were reported.
Characteristics of the Two Study Populations
One month after the third dose of vaccine, 99% of children in the 0-, 1-, and 6-month schedule group and 98% of those in the 0-, 12-, and 24-month schedule group developed anti-HBs titers of ≥10 mIU/mL (Table 2). None of the children were positive for antibody to hepatitis B core antigen. Before the third dose, the anti-HBs GMC was somewhat lower for recipients of the 0-, 1-, and 6-month schedule than for those of the 0-, 12-, and 24-month schedule, but the anti-HBs GMC was higher in this group 1 month after the third dose. Nevertheless, the antibody concentrations were very high in both groups. The reverse cumulative distributions of anti-HBs concentrations after the third dose are shown in Fig 1.
Antibody Response to Hepatitis B Vaccine Administered at 0, 1, and 6 Months or 0, 12, and 24 Months
Reverse cumulative distribution functions of anti-HBs concentration 1 month after third dose by immunization schedule.
The relationships of gender, race, mean BMI, and age at enrollment were assessed in regression analyses (Table 3). When entered individually, schedule, age >11 years, and mean BMI each were significantly related to antibody concentration after the third dose. Because of small numbers of black children and the lack of significance of the race variable, it was omitted from the multivariate analysis. In the multiple regression model, the importance of age decreased, attributable to the inclusion of BMI and the correlation between age and BMI. The anti-HBs concentrations in children >11 years of age were somewhat lower (28% [P = .20]) than the responses in younger participants. Children in the group receiving the 0-, 1-, and 6-month schedule had responses 87% higher than did those receiving the 0-, 12-, and 24-month schedule (P = .008). BMI was correlated inversely with final anti-HBs concentration. For every kg/m2 unit increase in mean BMI, antibody concentration decreased 12% (P = .0002; Fig 2).
Relative Effects of Schedule, Gender, Race, Age, and Mean BMI on Post-third Dose GMCs
DISCUSSION
Hepatitis B vaccine induced excellent antibody responses in children and adolescents when administered at schedules of either 0, 1, and 6 months or 0, 12, and 24 months. These data support the American Academy of Pediatrics and Advisory Committee on Immunization Practices recommendations that it is not necessary to restart immunization schedules when longer-than-recommended intervals occur between doses.1 ,3 ,8 Intervals between the first and second and second and third doses of ≤12 months result in an excellent antibody response. Although longer intervals between doses were not studied, there is no plausible reason to believe that longer intervals would not be effective. Yearly immunization is a convenient method of administering hepatitis B vaccine to children who were not immunized in infancy and who are at low risk of immediate exposure to hepatitis B infection. Children who are at high risk should complete the immunization after a 0-, 1-, and 4- to 6-month schedule. Also, immunization at yearly intervals was associated with lower completion rates than was immunization at 0, 1, and 6 months. Thus, the yearly interval schedule should be considered an acceptable option, not the preferred schedule.
These results provide reassurance to providers who are immunizing high-risk adolescents and young adults in sexually transmitted disease clinics and other settings.9 Although this population is known to be relatively poor at maintaining compliance to strict schedules, administering the first dose of vaccine at the first visit and subsequent doses whenever possible should result in high levels of protection. Of the children, ∼90% had protective anti-HBs concentrations after only 2 doses of vaccine.
The anti-HBs responses observed in this study are consistent with the response to 10-ug doses of Engerix-B vaccine reported in other adolescent studies10 and should provide long-term protection.11 Although the 0-, 1-, and 6-month schedule induced a higher GMC and a right-shifted reverse cumulative distribution, similar percentages of subjects in both groups had protective antibody concentrations and the GMCs were many times higher than observed after vaccination of children <1 year of age. The clinical significance of differences in GMCs is uncertain, as is the need for booster doses some time in the future. Currently, booster doses are not recommended. Therefore, although the the difference in GMCs is statistically significant, it is not clinically relevant.
Although this study included only a small number of nonwhite participants, the response to hepatitis B vaccines has been very good in all ethnic and racial groups,1 ,7 and the observations regarding intervals between doses should be widely applicable.
The effect of age on the response to hepatitis B vaccines has been demonstrated in persons >20 years of age.1 ,2Although it was relatively small, we observed an age effect during the middle childhood years in the univariate analysis. Similarly, the effect of body mass on antibody response has been demonstrated in adults but has not been evaluated in healthy children. This study demonstrates a strong inverse correlation between BMI and final anti-HBs concentration in children. After adjustment for BMI, the effect of age was not significant. Because BMI increases with age, the effect of BMI should be taken into consideration when assessing the response to all vaccines by age. The explanation for the association between BMI and response to vaccines has not been elicited fully but may be related to hormonal factors or as yet undefined differences in immune function as well as to the possibility that some vaccine could have been injected into subcutaneous fat in which absorption is diminished.12
ACKNOWLEDGMENTS
This study was funded by a grant from SmithKline Beecham Pharmaceuticals, Collegeville, PA.
We thank Christine Watts, Christine St. Ours, Stephen Lambert, and Natasha Khudya Kora (Centers for Disease Control and Prevention, Atlanta, GA) for technical assistance.
Footnotes
- Received December 3, 1997.
- Accepted December 10, 1998.
Reprint requests to (N.A.H.) Department of International Health, Johns Hopkins University School of Hygiene and Public Health, 615 N Wolfe St, Baltimore, MD 21205. E-mail: nhalsey{at}jhsph.edu
REFERENCES
- Copyright © 1999 American Academy of Pediatrics
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