Since the introduction of the hepatitis A vaccine in the mid-1990s, hepatitis A
incidence in the United States has fallen precipitously. During the prevaccination era
(i.e., 1980–1995), approximately 22,000–36,000 cases of hepatitis A were
reported annually in the United States.(1) From 1996 through 2006, the Advisory Committee on Immunization
Practices incrementally expanded hepatitis A vaccine recommendations from groups at high
risk of infection to universal vaccination of children aged ≥12
months.(1) Since then, the
number of hepatitis A cases in the United States has decreased approximately 90%, from
13,397 in 2000 to 1781 in 2013; incidence was lowest among persons aged <19
years.(2)
Two doses of inactivated hepatitis A vaccine are highly immunogenic in virtually
all healthy children and adults, resulting in postvaccination concentrations of antibody
to hepatitis A virus (anti-HAV) that are likely to persist at protective levels for at
least 30 years.(3) In contrast, among
infants born to anti-HAV-positive mothers (from either natural infection or
vaccination), the presence of passively acquired maternal anti-HAV may persist until age
12 months and may substantially reduce hepatitis A vaccine immunogenicity.(4–6)
Alaska became the first US state to institute universal hepatitis A vaccination
for all children in 1996, at which time Alaska Native persons had the highest incidence
of acute hepatitis A in the United States. Passively acquired maternal antibody occurs
in populations with endemic HAV infection and in whom the majority of infections occur
in children. In light of concerns about interference of maternal antibody with hepatitis
A vaccine immunogenicity, the Centers for Disease Control and Prevention (CDC) and the
Indian Health Service identified a need to determine the optimal immunization schedule
for American Indian/Alaska Native infants as well as all other infants and children. In
1997, the Alaska Native Tribal Health Consortium and the CDC began a study in infants
and children aged 6–24 months to determine the best age at which to begin to
administer this vaccine, the early results of which informed the decision of the US Food
and Drug Administration to lower the age of hepatitis A vaccine initiation from 24
months to 12 months [7]. Subsequently, the objective of continued follow-up of the
original cohort has been to determine whether administration of hepatitis A vaccine in
early childhood will provide long-term protection into adulthood, when clinical icteric
hepatitis is a greater risk after exposure. Follow-up of this cohort by testing anti-HAV
titer has been conducted through 15 years after the primary immunization series; herein,
we describe these most recent findings.
Patients and MethodsSTUDY POPULATION AND VACCINATIONParticipants included in this follow-up study were adolescents originally
enrolled as infants and young children between the ages of 6 months and 15
months in a phase 4 immunogenicity study reported by Bell et al.(7) In that study, participants
were recruited among mothers and their infants who received care in the prenatal
and pediatric clinics of the Southcentral Foundation Primary Care Center at the
Alaska Native Medical Center in Anchorage, Alaska, and the Anchorage
Neighborhood Health Center. Mothers provided informed consent and were tested
for total anti-HAV using a standard, commercially available assay (HAVAB; Abbott
Laboratories, Abbott Park, North Chicago, IL). Among mothers testing positive
for anti-HAV, hepatitis A vaccination status was confirmed by state vaccine
registry. Infants and young children were then randomized to receive two doses
of inactivated hepatitis A vaccine (HAVRIX, 720 enzyme-linked immunosorbent
assay units per dose; Glaxo SmithKline Biologicals, Rixensart, Belgium) on three
different schedules: at ages 6 and 12 months (group 1), 12 and 18 months (group
2), and 15 and 21 months (group 3). Within each group, subjects were stratified
to achieve a relatively equal number of children born to anti-HAV-positive and
anti-HAV-negative mothers. The study was approved by the institutional review
boards of the Alaska Area Indian Health Service and the CDC, by two Alaska
Native Health Boards (Alaska Native Tribal Health Consortium and Southcentral
Foundation), as well as by the US Food and Drug Administration under an
Investigational New Drug Application phase 4. Participants also received other
routine recommended vaccinations during the study period.
SAMPLING TIME POINTS AND MEASUREMENT OF ANTI-HAVSerum samples were collected from study participants beginning at 1 month
and 6 months after the second hepatitis A vaccine dose and postvaccination
follow-up at ages 3 years, 5 years, 7 years, 10 years, 12–14 years, and
15–16 years (a total of eight sampling time points). Serum samples
obtained through age 10 years were tested for anti-HAV in 2010 by the Assay
Development and Diagnostic Reference Laboratory of the Division of Viral
Hepatitis, CDC, and for the most recent study follow-up (i.e., among
participants aged 12–14 and 15–16 years), at the CDC Arctic
Investigations Program Laboratory in Anchorage, Alaska. Both labs used the
ETI-AB-HAVK-PLUS enzyme immunoassay diagnostic kit in accordance with the
manufacturer’s instructions (DiaSorin Inc., Stillwater, MN). The
ETI-AB-HAVK-PLUS High Positive Control, containing 1200–2000 mIU/mL
anti-HAV-WHO 2nd International Standard (1998), was serially diluted; and
dilutions were used as calibrators in the assay to quantify total anti-HAV in
the measuring range between 5 mIU/mL and 80 mIU/ mL. Serum samples with total
anti-HAV levels >80 mIU/mL were further diluted as necessary to determine
the actual anti-HAV levels. Geometric mean concentrations (GMCs) of anti-HAV
were calculated using levels obtained from all participants, not only those who
were seropositive.
DATA ANALYSISThe original study was designed with a sample size of at least 30
subjects per subgroup (60 subjects per group), which resulted in 80% power to
detect at least a two-fold difference in anti-HAV GMCs between subgroups in each
group (alpha = 0.05, two-sided). For the long-term follow-up study, only
children enrolled at the Alaska Native Medical Center were invited to
participate. Participants were excluded from further study if they received
additional doses of hepatitis A vaccine (n = 11) or moved away from Anchorage (n
= 60).
Anti-HAV levels were log-transformed before the statistical analysis.
Antibody levels below the lower limit of detection of the assay were assigned a
value of 5 mIU/mL. Comparisons of log anti-HAV levels by vaccination schedules
and by maternal anti-HAV status at each time point were made using linear
regression analysis. We analyzed the data according to vaccination schedule and
maternal anti-HAV status and, among group 1 infants, by source of maternal
anti-HAV (natural infection versus vaccine-induced). GMCs were calculated by
taking the log transformation of the estimated anti-HAV levels.
Subjects with anti-HAV levels ≥20 mIU/mL were considered
seropositive. The proportion of study subjects who were seropositive was
compared within and among groups at the various sampling time points using
logistic regression. Correlation between log anti-HAV levels at each time point
and peak log anti-HAV levels (i.e., 1 month after second dose) through
15–16 years of age were measured with the Pearson correlation. Analyses
were performed in SAS, version 9.2.
We also developed a random effects model of ln(anti-HAV) levels over
time. Fractional polynomials were used to determine the functional form of the
time since vaccination curve; we included all data points after the initial
1-month follow-up, which enabled the initial postvaccination anti-HAV level to
be used as a predictor in the model and which fit the data well for the range of
observed data.
ResultsSTUDY POPULATION AND FOLLOW-UPOf 311 infants and young children randomized in the original study, 183
participants were included in the long-term follow-up study (which began at age
3 years); 99 (50%) were males, and 189 (96%) were Alaska Native/American Indian.
Sixty-two (31%) participants had results available at all eight time points, 161
(81%) had results at five or more time points, and 181 (92%) had results at four
or more time points. The proportion of children with follow-up did not differ
significantly by vaccine group or maternal anti-HAV status.
PERSISTENCE OF ANTI-HAV AFTER HEPATITIS A VACCINATION: SEROPOSITIVITY AND
GMCSThe persistence of seropositivity after two doses of hepatitis A vaccine
(percentage of vaccine recipients with anti-HAV >20 mIU/mL) and anti-HAV
GMCs by study group and maternal anti-HAV status are shown in Table 1. The proportion of children in group 1 who
remained seropositive was consistently lower than that of children in groups 2
and 3 who remained comparably seropositive to each other during follow-up. For
example, the proportion of children who remained seropositive at age
15–16 years was 75% and 61% among group 1 children of anti-HAV-negative
and anti-HAV-positive mothers, respectively, compared with 100% and 67% among
children in groups 2 and 3. Regardless of group, the proportion who remained
seropositive was lower consistently among maternal anti-HAV-positive than
maternal anti-HAV-negative children. Compared with children in group 1, a
significantly higher proportion of children in groups 2 and 3 remained
seropositive at ages 7 years, 10 years, 12–14 years, and 15–16
years (P= 0.006, P = 0.001,
P= 0.007, P= 0.009, respectively) among
children of anti-HAV-negative mothers and ages 10 years and 12–14 years
(P = 0.015 and P = 0.040, respectively)
among children of anti-HAV-positive mothers. Within each group, there were no
significant differences in the persistence of seropositivity between
participants born to anti-HAV-negative versus anti-HAV-positive mothers until
12–14 years of age, but significant differences appeared at 15–16
years of age for group 2 and group 3 children (100% for maternal
anti-HAV-negative versus 67% for maternal anti-HAV-positive, P
= 0.032 and P = 0.016, respectively).
There was a significant decrease in anti-HAV levels over time within
each group and maternal status category until participants reached age
12–14 years. Among group 1 children, GMCs were not statistically
different between ages 12–14 years and 15–16 years, irrespective
of maternal antibody status (37 mIU/mL and 49 mIU/mL among children of
anti-HAV-negative mothers and 20 mIU/mL and 27 mIU/mL among those of
anti-HAV-positive mothers). Group 1 children had consistently lower levels of
anti-HAV than children in groups 2 and 3. Among participants in groups 2 and 3
combined, GMCs were statistically lower with the passage of time except between
1 month after dose 2 and age 3 years among maternal anti-HAV-negative and
anti-HAV-positive children and among those with anti-HAV-positive mothers
between age 10 years and age 12–14 years. Regardless of study group,
children with a mother who was anti-HAV-positive had consistently lower anti-HAV
levels than children whose mothers were negative, but this difference was not
significant at any time point after age 7 years.
Anti-HAV levels were consistently higher among females than males. This
difference was statistically significant at every time point among group 2 and 3
children with no maternal anti-HAV and at the first two time points in group 1
children with mothers with no detectable anti-HAV. No gender differences were
observed with regard to seropositivity through 10 years of follow-up. However,
in the current follow-up, we found that the GMCs of maternal antibody-positive
(n = 11) and antibody-negative (n = 8) group 1 males at age 12–14 years
were <20 mIU/mL and that the GMC of maternal antibody-positive males in
groups 2 and 3 (n = 9) at age 15–16 years was merely 25 mIU/ mL.
When included in a linear regression model of ln(anti-HAV) at each time
point, group, maternal status, and gender all remained statistically significant
at every time point. The two-way interactions of each of these variables were
not statistically significant at any time point. Native ethnicity was not
significantly associated with anti-HAV levels at any time point.
Anti-HAV levels remained highly correlated with peak anti-HAV levels (1
month after second dose) through 15–16 years of age: Spearman rank
correlations with peak anti-HAV level during the most recent time points were
age 12–14 years (R = 0.51, P <
0.001) and age 15–16 years (R= 0.51,
P< 0.001).
EFFECT OF NATURAL VERSUS VACCINE-DERIVED MATERNAL ANTI-HAVTo determine whether there was a difference in the persistence of
anti-HAV among children in group 1 whose mothers were anti-HAV-positive as a
result of natural infection versus vaccination, the GMC levels at every time
point after the second vaccine dose were compared for children in the following
categories: (1) children of anti-HAV-negative mothers, (2) children whose
mothers were anti-HAV-positive due to previous HAV infection (i.e., natural
immunity), and (3) children born to mothers who were anti-HAV positive as a
result of vaccination received prior to pregnancy (Table 2). There were statistically significant
differences (P< 0.05) between the GMCs of the three
group 1 categories for the first three time periods and 12–14 years of
age but not for the other time points. These differences, when present, were
between group 1 children whose mothers had natural immunity to HAV (who had
lower GMCs) compared with the GMCs of maternal antibody-negative children and
children of vaccinated mothers.
PROJECTED DURATION OF ANTI-HAV SEROPOSITIVITY AFTER VACCINATIONResults from a random effects model of ln(anti-HAV) levels over time,
which included all data points after the initial 1-month follow-up, are
displayed in Fig. 1. Of the total number of
anti-HAV levels that would have been obtained if all study participants had been
sampled at all time points, 77% were actually obtained and included in the
model. Among participants sampled at age 15–16 years, 80% were
seropositive; of these, the model predicted that 84% would still be seropositive
at 30 years after the second vaccine dose. Overall the model predicted that 64%
of participants would be seropositive at 30 years.
DiscussionThis study is the first to report the effects of maternal anti-HAV status on
the persistence of anti-HAV seropositivity (i.e., ≥20 mIU/mL) through age
15–16 years after administration of two doses of inactivated hepatitis A
vaccine among three groups of infants and toddlers beginning at age 6–21
months. In contrast to the 10-year follow-up of this cohort, in which there was a
high frequency of seropositivity among all three study groups through age 10 years
(100% among groups 2 and 3 and >90% among group 1 children, irrespective of
maternal antibody status),(8) our
findings through age 15–16 years indicate a notable decline after age 10
years in the frequency of anti-HAV seropositivity, particularly among all group 1
children, who were vaccinated beginning at age 6 months (seropositivity
50%−75%), and among maternal anti-HAV-positive children in groups 2 and 3
(67%−87%). Among group 2 and 3 participants, who received their first of two
doses of vaccine at ages 12 and 15 months, respectively, anti-HAV seropositivity
remained >90% through age 15–16 years among all maternal
anti-HAV-negative participants. However, among group 2 and 3 maternal
anti-HAV-positive children, only 67% of participants were seropositive at age
15–16 years, even though group 3 maternal anti-HAV-positive children had
higher anti-HAV GMCs 1 month after dose 2 than any children in groups 1 and 2. It
appeared, then, that maternal antibody-positive status even affected the duration of
seropositivity among some participants who initiated vaccination at age 15 months,
despite the likelihood that levels of maternal anti-HAV among the majority of
vaccinees by that age should have been undetectable,(5,6,9,10) and that anti-HAV GMCs 1 month after dose 2 were similar
between group 3 maternal anti-HAV-negative versus anti-HAV-positive children (i.e.,
1613 mIU/mL versus 1577 mIU/mL, respectively). This phenomenon bears watching during
subsequent observations of this cohort, given the potential detrimental effect of
maternal anti-HAV on long-term maintenance of anti-HAV levels among persons
vaccinated early in life. In this study, there were no participants vaccinated at
ages 12 and 15 months (groups 2 and 3) whose maternal antibody positivity was the
result of vaccination, so we are unable to tell whether there would be any
interference among such infants in low HAV endemic countries, where recommendations
suggest hepatitis A vaccination beginning at age 12 months.(1,11)
Other investigators have examined the effect of maternal anti-HAV on infant response
to hepatitis A vaccination as well as the potential modification of the severity of
neonatal diseases afforded by the transfer of maternal antibody in utero. A review
of a number of studies involving hepatitis A vaccination of infants as young as age
6 weeks highlighted the difference in vaccine response according to maternal
antibody status. Although all the studies reviewed showed similar levels of
seroconversion after vaccination among infants, with GMCs well above “the
minimal protective level” irrespective of maternal anti-HAV status, maternal
antibody-negative infants had higher postvaccination GMCs than their
anti-HAV-positive counterparts.(12) Another review and separate commentary examined the influence
of maternal immunization on infant immune responses, in particular the potential
salutary effects of maternal vaccination on the prevention of illness during
pregnancy and subsequent modification of some infant infectious diseases after
delivery, when neonatal response to vaccination is limited.(13,14)
With regard to the present subject, it is conceivable that maternal hepatitis A
vaccination (if the mother is susceptible) could result in sufficient transfer of
anti-HAV to protect against infant HAV infection before initiation of the vaccine
series.
In countries with growing economies and improving living conditions, where
an epidemiologic shift from high to intermediate HAV incidence may evolve rapidly,
hepatitis A control programs may need to consider the age of hepatitis A vaccine
initiation based on maternal anti-HAV prevalence and the likelihood of HAV exposure
during early childhood.(15,16) We found that children in group 1
who received vaccination starting at age 6 months consistently had lower anti-HAV
GMCs than group 2 and 3 children during follow-up. Although GMCs for all three
groups (Table 1), regardless of maternal
antibody status, remained at or above the level of seropositivity through age
15–16 years, some children in maternal antibody-positive group 1 (50% [12/24]
at age 12–14 years and 39% [7/18] at 15–16 years) and groups 2 and 3
(33% [7/21] at age 15–16 years) had anti-HAV levels <20 mIU/mL.
Administration of hepatitis A vaccine to children aged <12 months might be
useful (1) in countries where HAV infection occurs early in life and (2) for
preexposure and postexposure prophylaxis for children aged 6–12 months if
immunoglobulin is not available,(5)
which might include children traveling with their parents to endemic regions for
prolonged periods of time. One month after the first vaccine dose in the original
phase 4 immunogenicity study of this cohort, 54% (anti-HAV GMC 49 mIU/mL) and 94%
(anti-HAV GMC 173 mIU/mL) of maternal antibody-negative and antibody-positive
infants who initiated hepatitis A vaccination at age 6 months were seropositive,
respectively. Future studies could examine the practical uses of the hepatitis A
vaccine for children aged <12 months under the aforementioned conditions.
To determine whether the source of maternal anti-body might affect the
persistence of anti-HAV among vaccinated infants, we examined the effect of
vaccine-induced versus naturally induced maternal anti-HAV on GMCs among group 1
children. Group 1 children whose mothers had natural immunity to HAV had lower GMCs
at all follow-up time points (except for age 15–16 years) than children whose
mothers had vaccine-induced immunity or children of anti-HAV-negative mothers,
although these differences were significant only for the first three time points and
at age 12–14 years. There were no significant differences in anti-HAV GMCs
between children of anti-HAV-negative and hepatitis A-vaccinated mothers. Notably,
as illustrated in Table 2, a substantial
proportion (58% [15/26]) of children from mothers who were anti-HAV-positive due to
natural infection were no longer seropositive from ages 10 through 15–16
years, whereas those of vaccinated mothers remained seropositive during follow-up
except for a smaller proportion (36% [9/ 25]) of children at ages 12–14 and
15–16 years who became seronegative. Thus, it appeared that maternal antibody
from natural infection had a more pronounced effect on the long-term persistence of
anti-HAV than did maternal antibody from vaccination. As hepatitis A viral infection
results in higher anti-HAV levels that than those produced by
vaccination,(6,7) it is likely that higher transplacental
anti-HAV levels among children of mothers with a history of HAV infection resulted
in more pronounced suppression of the immunologic response to hepatitis A
vaccine.(13) Although
experimental studies in mice have suggested that vaccines sharing similar epitopes
as those recognized by maternal antibodies might result in reduced infant vaccine
response,(17) such a
phenomenon was not evident in our study. It seems, however, with the passage of time
after vaccination, that seropositivity wanes among infant vaccinees of
anti-HAV-positive mothers, irrespective of the source of maternal antibody.
In this respect, it is worth noting that despite low overall hepatitis A
incidence in the United States, HAV infection still occurs among susceptible
persons, particularly among unvaccinated adults who were not exposed to HAV during
childhood. Although hepatitis A incidence has plummeted since introduction of the
vaccine, in 2013 a total of 1781 cases of hepatitis A were reported from 50 states
to the CDC, a 14% increase from 2012. This increase reflects cases identified during
a large hepatitis A outbreak from imported pomegranate arils consumed by
unvaccinated persons in several southwestern states and Hawaii.(2,18)
Another hepatitis A outbreak in the United States occurred in 2013 among
unvaccinated adults with developmental disabilities in group homes in
Michigan.(19) More
recently, an outbreak of hepatitis was identified among unvaccinated travelers
returning to the United States from the Caribbean coast of Mexico (CDC, unpublished
data). Coinciding with recent trends in HAV seroprevalence in the United States, in
which anti-HAV prevalence among adults has decreased (and susceptibility to
infection increased),(20,21) the majority of hepatitis A cases in these
outbreaks, and among incident hepatitis A cases nationwide,(2) occurred among adults. Whether such
susceptibility might apply to vaccinated persons who have lost anti-HAV with the
passage of time, such as vaccinated infants of anti-HAV-positive mothers, remains to
be seen. As is the case with persons who have lost antibody to hepatitis B virus
(HBV) surface antigen years after primary immunization, there is evidence to suggest
persistence of cell-mediated immune memory despite a decrease in anti-HAV among
persons vaccinated for hepatitis A.(22–25) If such
persons are exposed to HAV, the relatively long incubation period from exposure to
onset of illness (4–8 weeks) might result in time enough for cellular
immunity to mount a response sufficient to prevent symptomatic hepatitis. Indeed,
such a dynamic is operative in “breakthrough” HBV infection, in which
persons who have low or undetectable residual antibody to HBV surface antigen many
years after vaccination may develop serologic evidence of infection (i.e., antibody
to HBV core antigen) but do not have symptomatic illness or develop chronic
infection after HBV exposure. However, in contrast to the relatively low
transmission risk from breakthrough HBV infection among hepatitis B-vaccinated
persons, it is unknown whether breakthrough HAV infection could occur among
vaccinated persons and whether such persons, even those with asymptomatic
break-through infection, could infect susceptible persons.
We found anti-HAV levels to be consistently higher among female children.
Another study found that male sex was significantly associated with lower GMCs 10
years after receipt of three doses of inactivated hepatitis A vaccine among an
unselected sample of adolescents and adults.(26) In that study, as well as ours, no gender differences were
observed with regard to seropositivity through 10 years of follow-up. However, in
the current follow-up, we found that the GMC of group 1 males at age 12–14
years was <20 mIU/mL and that the GMCs among maternal antibody-positive males
in groups 2 and 3 at age 15–16 years were nearly at the threshold of
seronegativity. The clinical significance of this finding is unclear, although
follow-up of this cohort should continue to examine the frequency of seropositivity
according to sex to determine whether such differences persist.
Nonetheless, among our cohort of children vaccinated during infancy and
early childhood who were available for follow-up sampling, most (80%) maintained
seropositivity through age 15–16 years; of those who remained seropositive at
age 15–16 years, the model predicted that 84% would still be seropositive 30
years after the second vaccine dose. Thus, these data overall support current
universal childhood US hepatitis A vaccine recommendations (i.e., among children
aged 12 months-18 years, two doses of inactivated HAVRIX [0, 6–12 months] or
VAQTA [0, 6–18 months]) and do not suggest a need for vaccine booster doses.
Other modeling studies of adults vaccinated for hepatitis A have predicted similar
durations of sustained seropositivity.(27,28) In a recent
study, investigators applied mathematical modeling to predict that at least 95% of
persons vaccinated as adults would remain seropositive after 30 years and at least
90% would remain positive after 40 years.(29)
This study is subject to several limitations. As shown in Table 1, the number of participants who were sampled
through age 15–16 years from each of the categories and subcategories was
approximately one-half of those initially enrolled in the follow-up study, and not
all participants who remained had been sampled at all earlier time points.
Therefore, the reduction in sample size could have affected our ability to detect
statistically significant differences between subgroups; however, the number of time
points sampled did not differ significantly by group or maternal antibody status.
Second, maternal quantitative anti-HAV levels were not obtained in the original
immunogenicity study but may have provided a more nuanced understanding of infant
vaccine response, particularly with the assessment of the effect of maternal
antibody derived from vaccination versus natural infection on infant response to
hepatitis A vaccine. Third, the lowest anti-HAV level needed to confer protection
has not been determined.(24,25) Other studies have used a lower
limit of detection of anti-HAV that ranged, depending on the assay used, from 10
mIU/mL to 33 mIU/mL. As we used a level of 20 mIU/mL, our determinations of
seropositivity prevalence could have been comparatively too high or low. Other
investigators have highlighted the variability among anti-HAV assays at relatively
lower levels of antibody, which may affect assessment of seropositivity based on
specific cutoff values(30);
however, it is likely that such an effect was mitigated by our using the same assay
for all study samples. Fourth, as our study cohort was comprised of Alaska Native
children, the results we obtained may not be representative of other populations
with different racial and ethnic compositions. However, previous vaccination studies
have shown no difference in response to vaccination between Alaska Native persons
and persons of other races/ethnicities.(24)
In conclusion, this study demonstrated that seropositivity to hepatitis A
persisted until at least age 15–16 years for most persons who initiated
vaccination at age 6–21 months, and modeling suggested that seropositivity
should persist for most persons for at least 30 years. Overall, these data support
current US hepatitis A vaccine recommendations and do not suggest a need for vaccine
booster doses. However, the prevalence of seropositivity among vaccinated infants
and children whose mothers were anti-HAV-positive decreased after age 10 years; at
ages 12–14 and 15-years, one of three such children no longer had levels of
anti-HAV above 20 mIU/mL. Continued follow-up of this cohort will be valuable to
determine whether the prevalence of seropositivity continues to decrease, regardless
of maternal antibody status. To determine whether breakthrough infection among
persons vaccinated for hepatitis A occurs, it is critical for hepatitis surveillance
programs to determine the vaccination status of all reported cases of acute
hepatitis A.