We describe herein the results of a study of hepatitis B immunity and the response to a single challenge dose among college students in a setting where universal hepatitis B vaccination at birth has been recommended for over 20 years. Consistent with studies among similar-age birth dose cohorts in settings of historically intermediate to high hepatitis B endemicity, nearly 90% of the students had a residual anti-HBsAg level of <10 IU/liter approximately 20 years after the primary vaccination series (2
). Although we had no previous serologic test results among the participants to determine when HBV exposure may have occurred, only two students were anti-HBcAg positive (only one of these two had documented hepatitis B vaccination dates) and both were negative for HBsAg and HBV DNA.
To our knowledge, this is only one of a few studies to have reported a differential response to a challenge dose among persons with an anti-HBsAg level of 0 IU/liter compared to those with levels of 1 to 9 IU/liter at the baseline. A study in Taiwan that was published in 2007 showed a statistically significantly stronger response in persons with any detectable anti-HBsAg than in those without detectable anti-HBsAg at the baseline (5
), although these participants had received four doses of plasma vaccine. In our case, students with a baseline anti-HBsAg level not equal to 0 IU/liter (though still <10 IU/liter) were significantly more likely to achieve a postchallenge anti-HBsAg level of ≥10 IU/liter than were those with a baseline level of 0 IU/liter; postchallenge anti-HBsAg GMCs were 10 times higher among those with any detectable anti-HBsAg at the baseline than among those whose baseline anti-HBsAg was 0 IU/liter. As the primary anti-HBsAg responses of these students to vaccination were not known, some with a baseline anti-HBsAg level of 0 IU/liter could have been primary nonresponders to hepatitis B vaccination or perhaps were never vaccinated for hepatitis B at all. For such students, the receipt of a single vaccine dose might not result in an antibody response of ≥10 IU/liter (1
Although the results of this study are consistent with others conducted in similar populations, the findings should be interpreted with caution. First, the study is in large part ecological, and the sample population represented only a minority of the students enrolled at the college. Of the participating students, a substantial number lacked or had incomplete vaccination records available to document dates of receipt of hepatitis B vaccine. However, hepatitis B vaccine coverage was reportedly high during the late 1980s in American Samoa (4
), and the baseline anti-HBsAg levels and responses to a challenge dose of those with levels of <10 IU/liter at the baseline did not differ greatly between those with and those without documentation of hepatitis B vaccination dates, suggesting that some, if not most, with missing or incomplete records likely received the vaccine on schedule, according to guidelines. Lastly, the package insert for the VITROS ECi anti-HBsAg assay used for this study states that anti-HBsAg levels of <5 IU/liter are “negative” and levels of ≥5 and <12 IU/liter are “indeterminate” (6
); nonetheless, we found a statistically significant difference in the response to a challenge dose between students with a baseline anti-HBsAg level of 0 IU/liter and those with levels of 1 to 9 IU/liter. Moreover, as shown in and , study participants who had levels of 1 to 9 IU/liter at the baseline (most of whom had a baseline anti-HBsAg level of <5 IU/liter) never had a postchallenge anti-HBsAg level of 0 IU/liter. This supports our contention that anti-HBsAg levels of 1 to 4 IU/liter, although considered “negative,” in this study appeared truly distinct from a value of 0 IU/liter.
Among adults who received hepatitis B vaccine in the remote past but who have an ongoing risk of HBV exposure in the future, there is value in the ability to identify those who retain immune memory despite having had a decrease in anti-HBsAg to a level of <10 IU/liter. In addition to the protection of those at risk of infection, there is an interest in conserving the resources—additional vaccine doses, serologic tests, and appointments at student or occupational health clinics—often necessary to identify such persons. Future studies with larger sample sizes might compare the performance of this and other anti-HBsAg assays at the lower levels of detection. Also, studies that aim to identify correlates of cellular immunity to hepatitis B among persons vaccinated in the remote past might consider comparing persons with and those without detectable residual anti-HBsAg, rather than examining all persons with levels of <10 IU/liter as a homogeneous group. From a clinical practice standpoint, the cost-effectiveness of a differential approach to the revaccination of persons found to have an anti-HBsAg level of <10 IU/liter could be compared between those with a level of “zero” and those with a level of “not zero” many years after primary immunization. Most importantly, ongoing surveillance or periodic serosurveys are needed to detect breakthrough infections and illness among health care personnel, health professional students, and other vaccinated persons at risk of HBV exposure to ensure the long-term effectiveness of hepatitis B vaccine.