The purpose of this study is to determine immune status of adolescents who responded to a
primary series of recombinant hepatitis B vaccine given at birth and to assess their
response to a booster dose of vaccine.
In the 1970s, Alaska Natives had the highest rate of hepatitis B virus (HBV) infection in
the US. Because of this, routine vaccination for all Alaska Native infants beginning at
birth was implemented in 1985. Hepatitis B vaccination programs have resulted in significant
declines in acute and chronic HBV infections among Alaska Natives, with virtually no new
chronic infections observed among the vaccinated cohort. Since 1991, the American Academy of
Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP) have
recommended hepatitis B vaccination for all infants, preferably beginning at birth.
Beginning vaccination during infancy prevents childhood acquisition of HBV, and provides
immunity against HBV before individuals reach an age where they may be at increased risk of
exposure due to high-risk behaviors (i.e., sexual activity and drug use) or occupation.
The success of this vaccination strategy is contingent on the vaccine being able to induce
long-lasting protection. The duration of protection conferred by hepatitis B vaccination
initiated at birth is not firmly established. Over 95% of vaccinees in clinical studies
develop a response to the three-dose primary hepatitis B vaccination series, defined as the
development of antibody to hepatitis B virus surface antigen (anti-HBs) to concentrations
greater than10 milliInternational Units per milliliter (mIU/mL) in blood. Within 5-10 years
after the primary series, anti-HBs concentrations decline and for many vaccinees,
concentrations will fall below 10mIU/mL, or even below detectable levels.
However, despite low anti-HBs concentrations, HBV infections (as measured by the presence of
markers of infection such as hepatitis B surface antigen [HBsAg] or antibody to hepatitis B
core antigen [anti-HBc]) are rare in persons who have been shown to respond to the primary
vaccine series. Continued protection against HBV infection in these children is likely
provided by immune memory cells generated at the time of the primary series. An immunologic
memory response (also termed an anamnestic response) can be evaluated by measuring the
effect of an additional (booster) dose of hepatitis B vaccine. An anamnestic response is
generally defined as a rapid (within 14-30 days) two-fold or greater increase in the
anti-HBs titer to at least 20mIU/mL. This signifies that immune memory cells capable of
generating a rapid rise in anti-HBs are still functional and would protect against HBV
infection. Blood tests that can identify memory B cells that are specific for vaccine
antigens are now available, and could be used to provide additional evidence of immune
Although there is good evidence that the immunologic memory for HBsAg exceeds the
persistence of measurable antibodies, few studies have examined lasting protection (>10
years) against HBV infection in a low-risk population vaccinated at birth with recombinant
vaccine.10 Most studies demonstrating long term protection from infection and persistent
immune memory despite low anti-HBs concentrations have been performed among children living
in areas where HBV infection is endemic, or whose mothers had chronic HBV infection (i.e.,
children at high risk of perinatal or childhood HBV infection). Studies conducted among
Alaska Native children have demonstrated that "low-risk" children (i.e., infants who were
born to HBsAg-negative mothers with no HBsAg-positive persons living in their households)
also have concentrations of anti-HBs that fall below 10mIU/mL during later childhood. In a
cohort of 36 children known to have responded to a recombinant vaccine series starting at
birth, none retained levels of anti-HBs ≥ 10mIU/mL at 7.5 years of age. In addition, three
of these children failed to exhibit an anamnestic response to a booster dose given at an
average age of 7.5 years.
At the present time, neither measurement of anti-HBs concentrations nor booster dose(s) are
recommended for low-risk children after the hepatitis B vaccine primary series given during
infancy. Low-risk Alaska Native children who received recombinant hepatitis B vaccination
starting at birth are now reaching adolescence, a period when the risk of HBV infection
through sexual transmission or transmission by injecting drug use is more likely to occur.
More information is needed to determine if protection against HBV infection among children
entering adolescence is adequate or if booster dose(s) might be necessary.
The specific objectives are as follows:
1. To determine anti-HBs concentrations among adolescents aged 11-14 years old who
responded to a primary series of recombinant hepatitis B vaccine initiated at birth.
2. To assess the anti-HBs response to a booster dose of recombinant hepatitis B vaccine
among adolescents who have been previously shown to respond to a primary series of
recombinant hepatitis B vaccine initiated at birth.
3. To determine whether specific immune memory cells are present among the study cohort
1. To correlate the response to a booster dose of hepatitis B vaccine with
1. initial response to the primary series
2. concentration of anti-HBs and age at time of a booster dose.
2. To document side effects in persons receiving a fourth dose of hepatitis B vaccine.
3. To determine the proportion of children who received and responded to a primary vaccine
series in infancy who subsequently became infected with HBV as demonstrated by the
presence of anti-HBc and/or HBsAg.
- Eligible children are those who received the 2.5 µg/dose three-dose series of
Recombivax HB® with the first dose having been given during the first week of life
and the series completed by 9 months. All children were born to HBsAg
- negative mothers, had no HBsAg-positive persons living in their households at the
time of immunization, and had a minimum of one serologic specimen prior to the age of
18 months with results indicating an anti-HBs concentration of ≥10mIU/mL.
- Receipt of a fourth dose of any hepatitis B vaccine
- History of allergic reaction after receiving hepatitis B vaccine or hypersensitivity
to any components of the hepatitis B vaccine used for the booster dose
- History of hepatitis B virus infection
- Existence of disease known to affect the immune system (e.g., HIV, AIDS, SCID,
chronic renal disease, cancer)
- Current or recent (within 6 months) receipt of immunomodulatory therapy (e.g.,
systemic corticosteroids, chemotherapy) or blood products