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Hepatitis B Vaccine Administered to Children and Adolescents at Yearly Intervals

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Hepatitis B Vaccine Administered to Children and Adolescents

at Yearly Intervals

Neal A. Halsey, MD*; Lawrence H. Moulton, PhD*; J. Crossan O’Donovan, MD‡; J. Ronald Walcher, MD§; Mary Lou Thoms, RN, DrPH*; Harold S. Margolis, MD¶; and David S. Krause, MD\

ABSTRACT. Objective. Hepatitis B vaccines are usu-ally 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 recip-ients of Engerix-B hepatitis B vaccine administered at 12-month intervals to the response to vaccine adminis-tered 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 vac-cine, 92.3% of children who received vaccine on the 0-, 1-, and 6-month schedule and 88.8% of children who re-ceived 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 sched-ule, 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 sched-ule (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 concentra-tions >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 in-versely 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.Pediatrics1999;103:1243–1247;

vac-cine, hepatitis B, hepatitis B vacvac-cine, antigen, dose, sched-ule, immunization, adolescent.

ABBREVIATIONS. GMC, geometric mean concentration(s); anti-HBs, antibody to hepatitis B surface antigen; BMI, body mass index.

H

epatitis B virus vaccines provide highly ef-fective 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 Pediat-rics and the US Public Health Service Advisory Com-mittee on Immunization Practices.3,4Hepatitis B vac-cine 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.5The recom-mended 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 ad-ministered 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 Increas-ing 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.6,7Because 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),

From the *Department of International Health, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland; ‡Drs. O’Donovan, Ahluwalia and Fertsch, Baltimore, Maryland; §Private Practice, Towson, Maryland; ¶Hepatitis Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Con-trol and Prevention, Atlanta, Georgia; and\SmithKline Beecham Pharma-ceuticals, Collegeville, Pennsylvania.

Received for publication Dec 3, 1997; accepted Dec 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: [email protected]

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3) previous immunization with hepatitis B vaccine, 4) febrile ill-ness (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.8In the analyses, the mean BMI from the two measurements in the analyses was used. Age was ren-dered a dichotomous variable, coded 1 for.11 years old (approx-imately 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 (10m, the licenced dose for 5- to 16-year-old children; hepatitis B vaccine, recombinant, SmithKline Beecham Pharmaceuticals, Philadelphia, PA) was administered intramus-cularly 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.1The 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 physi-cian if any reactions other than a sore arm occurred. At the next study visit, the child and parent(s) were asked about hypersensi-tivity 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.1,2A 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

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 de-fined by receipt of all study immunizations and pro-vision of two blood specimens (Table 1). Those chil-dren who completed and those chilchil-dren who did not differed with respect to initial BMI (18.8 and 21.1, respectively;P 5 .006) and race (89% of white chil-dren completed the study, 64% of the chilchil-dren of other races did not; P 5 .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 chil-dren in the 0-, 12-, and 24-month schedule group received a third dose of vaccine by a nonstudy pro-vider. None of the children had a serious adverse reaction to the vaccine, and no unusual reactions were reported.

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 sched-ule 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 con-centrations were very high in both groups. The re-verse cumulative distributions of anti-HBs concen-trations after the third dose are shown in Fig 1.

The relationships of gender, race, mean BMI, and age at enrollment were assessed in regression anal-yses (Table 3). When entered individually, schedule, age .11 years, and mean BMI each were signifi-cantly related to antibody concentration after the third dose. Because of small numbers of black chil-dren 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

TABLE 1. Characteristics of the Two Study Populations

Schedule PValue

0-, 1-, 6-Month

0-, 12-, 24-Month

Enrolled 193 196

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concentrations in children .11 years of age were somewhat lower (28% [P5.20]) than the responses in younger participants. Children in the group ceiving the 0-, 1-, and 6-month schedule had re-sponses 87% higher than did those receiving the 0-, 12-, and 24-month schedule (P 5 .008). BMI was correlated inversely with final anti-HBs concentra-tion. For every kg/m2 unit increase in mean BMI, antibody concentration decreased 12% (P 5 .0002; Fig 2).

DISCUSSION

Hepatitis B vaccine induced excellent antibody re-sponses in children and adolescents when adminis-tered 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 be-tween doses.1,3,8Intervals between the first and

sec-ond and secsec-ond 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 immuniza-tion is a convenient method of administering hepa-titis 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, immuniza-tion 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 clin-ics and other settings.9Although this population is known to be relatively poor at maintaining com-pliance to strict schedules, administering the first dose of vaccine at the first visit and subsequent doses whenever possible should result in high lev-els of protection. Of the children, ;90% had pro-tective 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 protec-tion.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

Fig 1. Reverse cumulative distribution functions of an-ti-HBs concentration 1 month after third dose by immu-nization schedule.

TABLE 2. Antibody Response to Hepatitis B Vaccine Admin-istered at 0, 1, and 6 Months or 0, 12, and 24 Months

Schedule

0-, 1-, 6-Month 0-, 12-, 24-Month

Number 181 161

Before third dose

%$10 92.3 88.8

GMC 117.9* 162.1*

95% CI 90.4, 153.7 110.1, 238.8 1 mo after third dose

%$10 99.5 98.1

GMC 5687.4† 3158.7† 95% CI 4172.8, 7766.5 2194.4, 4546.6

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higher than observed after vaccination of children ,1 year of age. The clinical significance of differ-ences 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 num-ber of nonwhite participants, the response to hep-atitis B vaccines has been very good in all ethnic and racial groups,1,7 and the observations regard-ing intervals between doses should be widely ap-plicable.

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

tion 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 in-jected 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 Pre-vention, Atlanta, GA) for technical assistance.

TABLE 3. Relative Effects of Schedule, Gender, Race, Age, and Mean BMI on Post-third Dose GMCs

Variable Univariate Models* Multivariate Model†

Relative‡ Effect (%)

P

Value

95% CI Relative Effect (%)

P

Value

95% CI

Schedule

0, 1, 6 vs 0, 12, 24 80 .02 12, 190 87 .008 18, 197

Gender

Male vs female 222 .30 252, 26 221 .33

Race

White vs black 1 .99 272, 269

Age

.11 y vs#11 y 250 .005 269,219 228 .20 256, 19

Mean BMI per unit kg/m2 213 ,.0001 218,28 212 .0002 217,26

R25.084.

* Variables entered one at a time. † Variables entered simultaneously.

‡ Percent greater GMC for given characteristic.

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5. American Academy of Pediatrics, Committee on Infectious Diseases. Recommended childhood immunization schedule: United States, January–December 1999.Pediatrics. 1999;103:182–185

6. Jilg W, Schmidt M, Deinhardt F. Vaccination against hepatitis B: com-parison of three different vaccination schedules.J Infect Dis. 1989;160: 766 –769

7. Hadler SC, de Monzon MA, Lugo DR, et al. Effect of timing of hepatitis B vaccine doses on response to vaccine in Yucpa Indians.Vaccine. 1989;7:106 –110

8. Roome AJ, Walsh SJ, Cartter ML, et al. Hepatitis B vaccine respon-siveness in Connecticut public safety personnel.JAMA. 1993;270: 2931–2934

9. Weinstock HS, Bolan G, Moran JS, et al. Routine hepatitis B vaccination in a clinic for sexually transmitted diseases.Am J Public Health. 1995;85: 846 – 849

10. Schiff GM, Sherwood JR, Zeldis JB, et al. Comparative study of the immunogenicity and safety of two doses of recombinant hepatitis B vaccine in healthy adolescents.J Adolesc Health. 1995;16:12–17 11. Gesemann M, Scheiermann N. Quantification of hepatitis B

vaccine-induced antibodies as a predictor of anti-HBs persistence.Vaccine. 1995; 13:443– 447

12. Shaw FE Jr, Guess HA, Roets JM, et al. Effect of anatomic injection site, age, and smoking on the immune response to hepatitis B vaccination.

Vaccine. 1989;7:425– 430

TRIAL AND ERROR

October 30th marked the 50th anniversary of one of the main tools of scientific medicine: the modern clinical trial. Although the idea of testing drugs on a few people before inflicting them on everyone else was not original, Austin Bradford Hill’s publication of his trial of an antibiotic called streptomycin on patients suffering from tuberculosis set a new standard. It was, in the jargon, a randomized, controlled trial: ‘‘controlled’’ because only half the volunteers received the drug (the others remained untreated, acting as a benchmark, or ‘‘control’’ against which the effectiveness of the antibiotic could be assessed); and ‘‘randomized’’ because those who took the drug were chosen, as statistical sampling theory requires, at random.

The Economist.October 31, 1998

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DOI: 10.1542/peds.103.6.1243

1999;103;1243

Pediatrics

Mary Lou Thoms, Harold S. Margolis and David S. Krause

Neal A. Halsey, Lawrence H. Moulton, J. Crossan O'Donovan, J. Ronald Walcher,

Intervals

Hepatitis B Vaccine Administered to Children and Adolescents at Yearly

Services

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http://pediatrics.aappublications.org/content/103/6/1243

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DOI: 10.1542/peds.103.6.1243

1999;103;1243

Pediatrics

Mary Lou Thoms, Harold S. Margolis and David S. Krause

Neal A. Halsey, Lawrence H. Moulton, J. Crossan O'Donovan, J. Ronald Walcher,

Intervals

Hepatitis B Vaccine Administered to Children and Adolescents at Yearly

http://pediatrics.aappublications.org/content/103/6/1243

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

TABLE 1.Characteristics of the Two Study Populations
TABLE 2.Antibody Response to Hepatitis B Vaccine Admin-istered at 0, 1, and 6 Months or 0, 12, and 24 Months
TABLE 3.Relative Effects of Schedule, Gender, Race, Age, and Mean BMI on Post-third Dose GMCs

References

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