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PEDIATRICS Vol. 107 No. 5 May 2001, pp. 1065-1069
,
, and
From the * Adolescent and Sports Medicine Section, and
Section of Academic General Pediatrics, Department of Pediatrics,
Baylor College of Medicine, Houston, Texas; § Department of Pediatrics,
College of Physicians and Surgeons, New York, New York; Section of
General Pediatrics and Adolescent Medicine, Wake Forest University
School of Medicine, Winston-Salem, North Carolina; and the ¶ Division
of Adolescent/Young Adult Medicine, Harvard Medical School, Boston,
Massachusetts.
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ABSTRACT |
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Results
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Objective. To determine the effect of varying dosing schedules and predictor variables on the seroprotection rates and geometric mean titer levels resulting from the hepatitis B vaccination series among adolescents.
Methods. Adolescents received the hepatitis B vaccination
series at varying schedules according to their natural adherence
patterns. Data collected included participants' medication use;
chronic illness; use of cigarettes, alcohol, and marijuana; age;
race/ethnicity; and body mass index. Participants' dates of
vaccinations were recorded and titer levels for hepatitis B surface
antibody were drawn ~12 and 24 months after study enrollment. The
data for 498 participants were analyzed using 
2 tests,
Student t tests, logistic regression models, and
analysis of variance.
Results. Seroprotection rates among adolescents were not affected by late vaccinations. The only factors affecting the achievement of seroprotection ~12 and 24 months after the first vaccination were body mass index and the number of immunizations received. Increased time between doses 1 and 2 and doses 2 and 3 showed a trend toward correlating with increasing titer levels.
Conclusions. Although adolescents at risk of acquiring hepatitis B should receive the hepatitis B vaccination series in a timely fashion, late doses are not detrimental, and may be beneficial, to achieving high antibody levels against the hepatitis B virus. Key words: immunizations, adherence, body mass index.
Adolescents and young adults comprise the largest group of
people acquiring hepatitis B in the United States. Approximately 63%
of acute cases of hepatitis B reported occur in those between the ages
of 15 to 29 years.1 The Advisory Committee on Immunization
Practices has long suggested immunization of high-risk
adolescents against hepatitis B, and in 1997, the Committee expanded
its recommendations to suggest that all youth 0 to 18 years old
who have not previously been immunized against hepatitis B be
immunized.2
Several studies have examined the ability of preteens and teens to
comply with the 3-dose vaccination regimen required for hepatitis B
immunization in the absence of special immunization programs or
school-based initiatives.3-6 The findings have, in
general, been discouraging in terms of adolescents' abilities to
comply with a strict dosing schedule for the immunization series.
Middleman et al6 found that only 41.7% (a school-based
clinic population) to 47.6% (a hospital-based clinic population)
completed the vaccination series within 1 year, despite demonstrating
knowledge that the dosing schedule is 0, 1, and 6 months. Not only is
it difficult for adolescents to remember when to return on time for the
immunizations, they often do not complete the full series. Although
83% of inner city youth attending a teen clinic in Chicago reported
that they would complete the vaccination series, only 14% received all
3 doses of the vaccine.4 School-based programs have had
significantly better success with immunization completion rates up to
94% among teens and preteens,7,8 however, such programs
are not available in all areas.
Given the range of dosing schedules that result from adolescents'
inability to adhere to the traditional dosing schedule of the hepatitis
B immunization series (0, 1, and 6 months), it is unclear how changes
in dosing schedule affect the rates of seroprotection achieved from the
vaccination series. One previous study addressed the vaccine titer
levels resulting from inconsistent dosing schedules in the Yucpa Indian
population and found that younger age and increased time between the
first and third doses independently predicted better vaccine response
when controlling for multiple variables; however, this study did not
specifically study adolescents.9 Jilg et al10
examined the differences in seroprotection rates with dosing schedules
of 0, 1, and either 2, 6, or 12 months among a sample of medical
students and found that the longer the interval to the third dose, the
higher the resulting geometric mean titer. This study, however, did not
look at concurrent variations in the dosing schedule of the second
vaccination. A study among adults in Australia (mean age: 30.2 years)
who presented for sexually transmitted disease services also found that
varying the dosing schedule of the vaccine within an 18-month time
period did not significantly affect the rate of seroprotection achieved
from the vaccine.11
Studies in adults have examined other variables that may affect
seroprotection rates in those receiving the vaccine. Variables that
have been found to decrease seroprotection rates have included site of
injection (gluteal site of injection decreases rates),12
older age,12-15 obesity,13,15 cigarette
smoking,12,13,15 and the presence of a disease that alters
the immune system.11,15 No studies before the inception of
this study have addressed these variables in an adolescent population.
The purpose of this study was to observe the seroprotection rates
resulting from the dosing schedules determined by adolescents' natural
adherence patterns with the 3-dose hepatitis B immunization schedule.
In addition, we sought to determine the effect of other biological
variables on the achievement of seroprotection including smoking, body
mass index (BMI), chronic illness, and medication use.
Between December 1994 and November 1995, patients between the
ages of 11 and 24 years attending the Adolescent Medicine Clinic at
Children's Hospital, Boston, Massachusetts and those attending a
school-based teen health clinic in Cambridge, Massachusetts were
approached for enrollment in this hepatitis B vaccination study.
Patients who had a documented history of hepatitis B infection, were
pregnant at the time of enrollment, or had previously received the
hepatitis B vaccination series were not eligible for participation.
Informed consent was obtained for enrollment in the study and for the
administration of the vaccination series; parental consent by phone or
in person was required for participants under 18 years old. A
standardized education in either Spanish or English about hepatitis B
infection and the hepatitis B vaccination series, including the
standard dosing schedule of 0, 1, and 6 months, was given to all
participants. Participants completed a 40-item confidential,
self-administered questionnaire (offered in both English and Spanish)
that was linked later to titer data. The questionnaire had been pilot
tested among a small group of young adolescents (12-14 years old) for
readability. The questionnaire was administered to study participants
in the examination room at the conclusion of their health care visits.
Items on the questionnaire germane to this study included: demographic
information (gender, race/ethnicity), health risk behaviors (cigarette
and other substance use), the presence of a chronic illness (diabetes,
asthma, cystic fibrosis, migraine headaches, seizures, eating disorder,
or other with a fill-in space), and medication use (birth control
pills, vitamins, iron pills, steroids of any kind, or other with a
fill-in space). The cigarette and drug use questions were drawn from
the Youth Risk Behavior Survey conducted by the Centers for Disease
Control and Prevention, and the reliability of these questions has been
studied.16 Data regarding height, weight, and date of
birth were charted during the enrollment visit for the determination of
BMI and age.
After the questionnaire was completed, baseline laboratory tests
including hepatitis B surface antibody, surface antigen, and core
antibody were drawn to determine possible previous hepatitis B
infection or immunization (using AUSZYME Monoclonal, AUSAB EIA, and
CORZYME immunoassays, Abbott Laboratories, Abbott Park, IL). Participants who were surface antibody positive (n = 25) or surface antigen positive (n = 1) at baseline
were eliminated from this study. Before each subsequent vaccination and
~12 months and 24 months after enrollment (to be referred to as the
first and second titer follow-up visits, respectively), blood was drawn
to determine hepatitis B surface antibody titer levels (AUSAB
Quantitation Panel, Abbott Laboratories, Abbott Park, IL), and
the presence of hepatitis B core antibody was determined to rule out
intercurrent infection with the hepatitis B virus. Participants who
tested positive for hepatitis B core antibody at any visit were
eliminated from the study analyses.
The first hepatitis B vaccination was given intramuscularly in the
deltoid muscle. The vaccination given during the time period of the
study was Engerix (Smith-Kline Beecham, Houston, TX) and was provided
free of charge to the patients under the Vaccine for Children Program
from the state Department of Health and Human Resources. The
recommended dose at that time was 20 µg, or 1 mL, of vaccine. A
1-inch needle was used for all participants. Participants were informed
to return for their second and third vaccines 1 month and 6 months from
the date of enrollment. Reminder postcards were sent 5 months after a
missed vaccination and for the first and second titer follow-up visits.
A small incentive ($20 at the first titer follow-up visit and movie
passes at the second titer follow-up visit) was offered at the time of
the titer follow-up visits to encourage greater return rates.
Participants in the study who were late for vaccinations received them
whenever they returned to the clinics. Participants' vaccination times
were recorded in the study log and medical record. Vaccinations were not given before the expected date, and for those who were late for
dose 2, dose 3 was not given before 2 months after dose
2.17 Nine hundred and forty-three participants enrolled in
the study. Only eligible participants for whom the vaccinations were
documented with exact dates and doses and who had returned for the
first titer follow-up visit were included in these analyses
(n = 498). The first titer follow-up visits were
between 11 and 22 months after enrollment in the study with the
majority of participants (n = 465, 93.4%) obtaining
titer data between 11 and 15 months after enrollment. Second titer
follow-up data were obtained from 162 of the eligible participants,
ranging from between 22 and 36 months after enrollment. Because
specific geometric mean titer (GMT) level data are time-sensitive, only
those participants with first titer follow-up data obtained before 18 months from enrollment were included in the specific GMT analysis
(n = 486). The 151 of these eligible participants who
had second titer follow-up data available that was obtained before 30 months after enrollment were included in the analysis of second titer
follow-up data.
Statistical Analysis
The outcome variables examined in this analysis include: 1) the
achievement of seroprotection (a titer level of TABLE 1 TABLE 2
METHODS
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Methods
Results
Discussion
References
10 IU/L) at the first
titer follow-up visit (a dichotomous variable); and 2) the GMT
of antibody to hepatitis B surface antigen at the first and second
titer follow-up visits after enrollment. The specific GMTs for the
titer follow-up visits reported in Tables 1, 2, and 3 include the data
from participants who had the reported number of vaccinations and no
additional vaccinations 3 months before the first titer follow-up
visit and 3 months before the second titer follow-up visit. This was
done to control for the complex exponential relationship associated
with titer level rise and subsequent decay that occurs shortly after a
booster dose of vaccine.18
GMT Levels for Participants Receiving One, Two, and Three Immunizations
GMT at First Titer Follow-Up Visit of Participants Whose Times to the
Second of Two Immunizations Varied*
Predictor variables examined in the analysis pertaining to seroprotection included: age; gender; race/ethnicity; vitamin, oral contraceptive, and iron pill use; presence of a chronic illness (because of a small numbers of patients reporting a chronic illness, the variable was dichotomized to indicate whether the patient reported any chronic illness); alcohol, cigarette, and marijuana use; BMI; number of immunizations received; time in months between the first and second vaccinations; time in months between the second and third vaccinations; and total time to complete the vaccination series.
Statistical tests included frequencies, 2
analyses, Student's t test, logistic regression models, and
analysis of variance. Analyses were completed using SAS for Windows
(SAS Institute Inc, Cary, NC).
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RESULTS |
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Of the 498 participants, 119 (24%) were male and 379 (76%) were female. Twenty-two percent were white, 43% black, 19% Hispanic, 1% Asian, and 15% self-reported as "other." The mean age of the group was 16.2 years (range: 11.1-24.9 years). Two hundred seventy-eight (55.8%) participants completed the series before the first titer follow-up visit, 162 (32.5%) received 2 immunizations, and 58 (11.7%) received 1 immunization. Regardless of dosing schedule, 98.6% of those who completed the series, 69.1% of those who received 2 immunizations, and 19.0% of those who received 1 immunization achieved seroprotection (see Fig 1).
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Factors Associated With Seroprotection
Using bivariate analysis, female gender (P = .02), oral contraceptive pill use (P = .005), lower BMI (P = .008), and number of immunizations received (P < .0001) were associated with greater likelihood of achieving seroprotection. Eighty-two percent of females versus 72.% of males, and 91% of oral contraceptive pill users versus 77% of nonusers achieved seroprotection. The mean BMI of those achieving seroprotection was less than the mean BMI of those not achieving seroprotection (24.1 vs 26.3). There were no significant associations of the achievement of seroprotection with age; race/ethnicity; vitamin pill or iron pill use; the presence of a chronic illness; or with alcohol, cigarette, or marijuana use.
To determine the impact of the time between the first and second immunizations on the achievement of seroprotection, the first logistic regression model predicted the achievement of seroprotection among the subpopulation of participants who had received only 2 vaccinations by the first titer follow-up visit (N entered into regression model = 151). The predictor variables that were significantly associated with the achievement of seroprotection on bivariate analysis (as noted above), in addition to the variable of the month of the second shot, were included in the initial modeling. BMI and the month of the second shot were included in the final regression model, and BMI was the only variable found to be significantly associated with the odds of achieving seroprotection. For each unit of decrease in BMI there was an 8% increased odds of seroprotection (odds ratio: 0.92, 95% confidence interval [CI]: 0.87-0.98). The time between the first and second vaccination did not affect the odds of achieving seroprotection.
A separate logistic regression model was performed using data from the subpopulation of participants who had received all 3 immunizations before the first titer follow-up visit (N entered into regression model = 277). The final model included the independent variables of BMI, month of the second shot, month of the third shot, and the interval between the second and third shots. Again, none of the variables associated with dosing schedule affected the achievement of seroprotection. BMI, however, remained a significant predictor of the achievement of seroprotection (odds ratio: 0.80, 95% CI: 0.68-0.95).
The Effect of Dosing Schedule on GMTs
GMT at the first and second titer follow-up visits for those who received 1, 2, and 3 immunizations are listed in Table 1; clearly the number of vaccinations received affects the final GMT. Of the 151 study participants for whom second titer follow-up data were available, more than 145 had completed the series 3 months before the second titer follow-up visit. Among a subset of participants for whom second titer follow-up data are available (n = 93) who completed their vaccination series by within 3 months of the first titer follow-up visit and received no additional boosters, the GMTs were 1718 (95% CI: 1060-2786) at the first titer follow-up visit and 1082 (95% CI: 698-1677) at the second titer follow-up visit.
To more closely examine the effect of dosing schedule on the GMTs achieved after vaccination, participants were stratified into various categories. One hundred fifty participants had received only 2 immunizations and no additional immunizations within 3 months before the first titer follow-up visit. The GMT levels at the first titer follow-up visit associated with the length of time between immunizations 1 and 2 are listed in Table 2. There is a statistically significant difference between the values for the 1- to 2-month group versus the 6- to 11-month- group. GMT levels increase with increased length of time between immunizations 1 and 2.
Of the participants from whom titers were drawn at the second titer follow-up visit who had received their second immunization within 2 months of the first immunization and the third immunization any time before 3 months of the second titer follow-up visit (thus controlling for the timing of the second dose and looking only at the effect of timing of the third dose), the GMT levels associated with the length of time to the third immunization are shown in Table 3. Although the difference between the GMT levels is not statistically significant, there is a trend toward increasing GMTs as the length of time between the second and third immunizations increases.
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DISCUSSION |
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Discussion
References
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This study of adolescents who received hepatitis B immunization within the context of usual clinical practice and who followed their natural adherence patterns found that rates of seroprotection from the immunization series were not greatly affected by a dosing schedule that included late vaccinations. In our study, higher BMI was significantly associated with lower rates of seroprotection. The cause of this effect is unclear. Shaw et al12 have postulated that there may be hormonal influences present among obese participants that may affect response, or perhaps the vaccine did not fully reach muscle but was instead injected into subcutaneous fat, thus decreasing immune response.
In contrast to studies of adults, smoking status did not affect the achievement of seroprotection among these adolescents. It is possible that the negative effect of smoking on immunologic response requires biological changes resulting from more long-term smoking behaviors. Adolescents may smoke fewer cigarettes per day than adults, thus making the negative effect of smoking more difficult to discern. In addition, our study specifically looked at the effect of age, gender, race/ethnicity, vitamin pills, oral contraceptive pills, and chronic illness (nonimmunologic) and found that these variables had no effect on the achievement of seroprotection among the adolescent participants.
Because this study followed the natural adherence patterns of adolescents, each category of analysis (number of months between vaccinations) may not have had adequate numbers of participants to achieve the power required to observe a statistically significant difference in GMT in all analyses; however, the findings of this study suggest that increased time between the first and second doses, as well as between the second and third doses of vaccine, is positively correlated with increases in GMT. Jilg et al10 found that when systematically studying the effect of time between doses 2 and 3, the resulting GMT rose with increased time between vaccination. In his study of participants 5 to 16 years old receiving the series at 0, 12, and 24 months, Halsey et al19 found that the resulting GMTs were higher in the group that followed the more protracted dosing schedule versus the standard 0-, 1-, and 6-month dosing schedule. Hadler,9 in his study of the Yucpa Indians, found that with regression analysis, time between doses 2 and 3 did affect titer levels, but time between doses 1 and 2 did not affect titer response.
In addition, Jilg et al10 notes in his study of different dosing schedules that second and third vaccinations given too close to the first dose do not act to boost the immune response as when doses are administered later. In a study by Marchou et al,20 titer levels in response to the hepatitis B vaccination series given within a very short time period continued to rise for several months before beginning their descent. Wilson and Nokes,21 in a recent article published in Vaccine, set forth a mathematical model of hepatitis B antibody kinetics suggesting that immune memory depends not only on response directly to antigen stimulation, but also on other cells that continue to clone even after the antigen is out of circulation. The accumulation may continue for months after the initial priming of the immune system.21 Thus, the longer the time period after priming that the clonal expansion has to continue, the larger the boosted response to another dose may be. This theory is supported by our data that reveal a greater GMT after longer periods of time between doses of vaccine.
A potential limitation of this study includes the dose of Engerix administered during the study. The dose of Engerix vaccine used was appropriate for the time period in which the study began (20 µg); however, dosing recommendations have since been changed to 10-µg vaccinations for those <19 years old. Several studies have been done supporting the use of lower-dose vaccines,19,22-25 thus there is little reason to believe that the overall results of this study (as governed by antibody kinetics) would vary significantly were it to be repeated using the 10-µg dose of vaccine.
This study strongly reinforces the flexibility allowed with the dosing schedule of the hepatitis B vaccination series among adolescents. The natural tendency among the adolescent age group is to postpone vaccination visits. There is mounting evidence that increasing the time between each vaccination may increase the adolescent's immune response to the immunization series. There is evidence that 2 doses of vaccine at higher dosing levels and a more protracted 0- and 6-month schedule confers immunity similar to 3 doses at the traditional dosing schedule to young adults receiving the vaccination series,26 further supporting the findings of our study as well as the theory set forth by Wilson and Nokes.21 A protracted schedule may not be appropriate for adolescents who may be at risk from sexual or drug use behaviors of acquiring the disease, as 1 or 2 vaccinations at traditional doses do not confer the same level of immunity as 3 vaccinations. Health care providers also need to be aware of the potential for decreased rates of seroprotection among patients with a higher relative body weight.
Given the divergence between the recommended immunization dosing schedule and adolescents' natural adherence pattern with the hepatitis B dosing schedule, it would be of benefit to examine the resulting differences in seroprotection rates with all immunizations provided to adolescents. The advent of the hepatitis A vaccination series, varicella vaccination series (2 doses for those >13 years old), Lyme vaccine, and other multidose regimens in development requires knowledge of the efficacy of these vaccines when given using variable dosing schedules. Studies are needed that will address factors of relevance to adolescents' lifestyles, adherence patterns, BMI, and medications to aid providers who are responsible for immunizing this challenging group of patients.
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ACKNOWLEDGMENTS |
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This study was supported in part by Project Numbers MCJ-489501 and MCJ-259195 from the Maternal and Child Health Bureau (Title V, Social Security Act); the Health Resources and Services Administration; the Department of Health and Human Services; Abbott Laboratories; the William F. Milton Fund; and the Deborah Munroe Noonan Memorial Fund.
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FOOTNOTES |
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This study was presented in part to the Society for Adolescent Medicine; March 1999; Los Angeles, CA; and to the Society for Pediatric Research; May 1999; San Francisco, CA.
Received for publication May 8, 2000; accepted Sep 5, 2000.
Address correspondence to Amy B. Middleman, MD, Texas Children's Hospital, 6621 Fannin St, MC 3-3340, Houston, TX 77030. E-mail:amym{at}bcm.tmc.edu
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ABBREVIATIONS |
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BMI, body mass index; GMT, geometric mean titer; CI, confidence interval.
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REFERENCES |
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United States.
MMWR Morb
Mortal Wkly Rep
1999;
48:33-34 [Medline]This article has been cited by other articles:
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  E. B. Walter, K. M. Neuzil, Y. Zhu, M. P. Fairchok, M. E. Gagliano, A. S. Monto, and J. A. Englund Influenza Vaccine Immunogenicity in 6- to 23-Month-Old Children: Are Identical Antigens Necessary for Priming? Pediatrics, September 1, 2006; 118(3): e570 - e578. [Abstract] [Full Text] [PDF]
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 K. C. Lee, J. A. Finkelstein, I. L. Miroshnik, D. Rusinak, J. M. Santoli, S. M. Lett, and T. A. Lieu Pediatricians' Self-reported Clinical Practices and Adherence to National Immunization Guidelines After the Introduction of Pneumococcal Conjugate Vaccine Arch Pediatr Adolesc Med, July 1, 2004; 158(7): 695 - 701. [Abstract] [Full Text] [PDF]
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I. M. Gonzalez, F. M. Averhoff, M. S. Massoudi, H. Yusuf, F. DeStefano, P. Kramarz, J. E. Maher, J. P. Mullooly, C. Chun, R. L. Davis, et al. Hepatitis B Vaccination Among Adolescents in 3 Large Health Maintenance Organizations Pediatrics, November 1, 2002; 110(5): 929 - 934. [Abstract] [Full Text] [PDF]
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