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PEDIATRICS Vol. 107 No. 4 April 2001, pp. 771-772
In October 1999 the Advisory Committee on
Immunization Practices (ACIP) recommended a new regimen for hepatitis B
immunization of individuals 11 to 15 years old, using two (2) 1.0-mL
10-µg doses of Recombivax (Merck Research Laboratories, Blue Bell,
PA) on a 0 and 4- to 6-month schedule.1 The Canadian
National Advisory Committee on Immunization made similar
recommendations in 2000.2 These recommendations were made
after the results of studies showing that 2 doses of vaccine were
similar in terms of antibody concentrations, seroprotection rates, and
rates of adverse events to 3 doses of vaccine. One limitation, however,
was that no data were available on the issues of long-term protection
or immune memory equivalence of the 2 schedules. The article by Cassidy et al3 in this issue of Pediatrics adds
meaningful and practical data to the ACIP recommendation for a 2-dose
adolescent hepatitis B immunization strategy, and provides an answer to
the question of immune memory induction by the 2-dose schedule.
In the study by Cassidy et al, 1026 adolescents 11 to 19 years old were
enrolled and randomized to 1 of 5 Recombivax active immunization groups
(10 µg at 0 and 4 months or 0 and 6 months, or 5 µg at 0 and 6 months or 0, 2, and 4 months or 0, 1, and 6 months).3 A
subset of study participants who had received 5-µg doses at 0 and 6 months or 0, 1, and 6 months had blood samples drawn 2 years after the
last dose to determine antibody persistence, and received a 5 µg
"booster" dose of vaccine to assess immune memory. The results
generally followed the large body of literature already known on the
major issues; namely that higher doses, 3 versus 2 doses, and longer
intervals between doses lead to higher antibody levels. However, the
results demonstrated no difference in the percent seroprotected
(defined as developing An important issue addressed in this study is that of induction of
immune memory. Anamnestic antibody responses were found in 92% of the
0- and 6-month schedule study participants, and 95% of the 0-, 1-, and
6-month study participants. The data of Cassidy et al provide
reassurance that immunologic memory, at least 2 years later, is present
and results in an anamnestic antibody response. In turn, this allows
confidence that a 2-dose immunization schedule is likely to be equally
effective in providing long-term protection against symptomatic
hepatitis B infection and chronic carriage of the virus.
Until recently, official recommendations were for 3 doses of vaccine on
a 0-, 1-, and 6-month schedule, regardless of age.6
Although this regimen is safe, immunogenic, and efficacious, it is
nonetheless both burdensome and expensive. The increasing number of
vaccines listed on the vaccine schedule, the increasing role of cost
issues, and the difficulty of delivering 3 doses over a 6-month time
period have all conspired to hamper efforts at fully protecting this
population against this vaccine-preventable disease. Difficulties in
delivering a full 3 doses are evidenced by a chart review performed at
the Kaiser Permanente adolescent clinic, which documented that only
11% of the adolescents counseled about the need for hepatitis B
vaccine (HBV) actually received 3 doses of the vaccine.7
Clinical and public health experience suggests that the number of
persons completing a vaccine series decreases as more doses are
included. The first large-scale school-based HBV program that attempted
to offer vaccine to over 43 000 students, while successful, nonetheless had over 5% (almost 2000 students) who did not complete the series, although this was a closely managed prospective
study.8 A statewide hepatitis B immunization program in
Oregon, targeting all adolescents 11 to 18 years old reported that
almost 92% of students completed 2 doses of vaccine, while only 84%
completed 3 doses.9 A recent report of students attending
either a clinic-based or school-based adolescent clinic in Boston
demonstrated that <50% of the study participants completed the 3-dose
series within 12 months of the first dose.10 In fact, by
26 months after the first dose, only 72% had received 3 doses of
vaccine while almost 88% had managed to receive 2 doses. Additionally,
study participants receiving Medicaid and study participants who were
not white had increased time to completion of the series, suggesting
that increased numbers of poor and minority participants at high risk
for infection, might be better protected with a 2-dose regimen.
As Cassidy et al point out, additional advantages of a 2-dose regimen
include reduced cost both of vaccine purchase, and the resources
necessary to deliver vaccine. Additionally, a regimen involving only 2 doses over a 4-month time period is likely to be better received
psychologically, and result in higher rates of compliance, than a
3-dose, 6-month regimen. As universal immunization is likely to occur
in school-based settings,11 a 2-dose, 4- to 6-month
schedule also allows for more realistic completion within a school
year, whereas a 3-dose schedule imposes constraints on timing of doses
within a given school year. In fact, the benefits of a 2-dose strategy
are congruent with the recommendations from a recent independent
nonfederal Task Force on Community Preventive Services designed to
improve vaccination coverage among children, adolescents, and
adults.12
Numerous studies have documented the relationship between diminished
antibody response to the vaccine and increasing age at the time of
receipt.13,14 Thus, an advantage to immunizing adolescents
that is not well-appreciated at the clinical or public health
population level are data demonstrating that increasing age has an
adverse effect on the rate of seroprotection as was also shown in this
current study.3 In this study, the authors demonstrate
that age was the single factor found in logistic regression analysis to
be associated with a lower proportion of participants achieving
antibody levels of A summary of the advantages that a 2-dose regimen offers includes: 1)
lower cost compared with 3 doses, 2) better compliance leading to
higher rates of immunity among the adolescent population-particularly hard to reach sub-populations,15 3) equal immunogenicity
in terms of seroprotection, compared with a 3-dose regimen 4) higher
rates of seroprotection after one (1) 10-µg dose compared with the
5-µg 3-dose regimen, 5) equal evidence of induction of immunologic
memory compared with the standard regimen, and 6) a potential safety
factor with less doses and less chance for an allergic or adverse
reaction. In addition, a 2-dose regimen allows for further efficiency
by making it possible to combine the hepatitis A and B vaccines into 1 formulation for adolescents, just as in infants.16
The work by Cassidy et al is an important observation and has
meaningful and practical clinical utility for health care providers who
care for adolescent patients. This data confirms previous data that led
to the ACIP recommendation for adolescents. All providers should adopt
the 2-dose regimen for adolescents 11 to 15 years old as it is safe,
effective, requires fewer visits and numbers of injections, and
therefore decreases health care costs. Nonetheless, caution dictates
that we should recognize the lack of data supporting this
recommendation for adolescents in specific groups, particularly those
with preexisting risk factors for vaccine failure.5,17
Whether such persons should have 2 or 3 doses is unclear. Prudence would suggest that if only 2 doses are administered to individuals at
high risk of vaccine failure, anti-HBs testing should be performed 1 to
3 months after the last dose to determine vaccine success or failure.
Having now achieved success with a 2-dose regimen, what the world
really needs is a 1-dose HBV.
10 mIU/mL of anti-hepatitis B surface
[anti-HBs]), after any of the regimens. Many practitioners may not be
aware that the absolute height of the antibody level may be clinically
less meaningful, compared with the percent who reach an anti-HBs
antibody level 10 mIU/mL.4,5 These data provide
additional confidence that higher antibody levels per se may be of less
importance compared with the rate of seroprotection induced by the
vaccine while allowing for fewer doses to be administered. Similarly,
no significant differences between regimens for any adverse experience
was found, with the exception of a posthoc comparison that found a
higher rate of transient injection site reactions after the first
10-µg dose, compared with the 5-µg dose (30% vs 19.9%;
P < .001).
10 mIU/mL of anti-HBs (P = .03)
and a lower geometric mean (antibody) titer (P < .001). Younger (age: 11-15 years) children demonstrated higher rates
of seroprotection and higher geometric mean (antibody) titers (twofold
higher) than children 16 to 19 years old. Thus, starting the series
before the age of 15 years, with the convenience of a 2-dose regimen,
offers enhanced and early seroprotection. By "getting 2 doses rather
than 3 doses later," the effect may be to decrease the age at which
the vaccine is sought by parents and encouraged by health care
providers, thereby improving rates of protection.
Mayo Vaccine Research Group
Mayo Clinic and Foundation
Rochester, MN 55905
FOOTNOTES
Received for publication Sep 21, 2000; accepted Sep 21, 2000.
Reprint requests to (G.A.P.) Department of Medicine, Clinical Pharmacology and Infectious Diseases, Mayo Vaccine Research Group, 611C Guggenheim Bldg, 200 First St SW, Rochester, MN 55905. E-mail: poland.gregory{at}mayo.edu
ABBREVIATIONS
ACIP, Advisory Committee on Immunization Practices; HBs, hepatitis B surface; HBV, hepatitis B vaccine.
REFERENCES
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