Poorolajal J
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran

Mahmoodi M
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran

Majdzadeh R
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran

Nasseri-Moghaddam S
Digestive Disease Research Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran

Haghdoost A
Community Medicine Department and Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran

Ghalichi L
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran

Fotouhi A
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran

Correspondence:

Jalal Poorolajal, M.D.
Department: Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences (TUMS)
City: Tehran
Country: Iran
E-mail: poorolajal@umsha.ac.ir
Tel: +98 21 6642 1746
Fax: +98 21 6642 1746

Background and Aims: The duration of protection provided by hepatitis B (HB) vaccine is still unknown but can be estimated indirectly by measuring the anamnestic immune response to booster doses of the vaccine.

Methods: We searched electronic databases and conference databases up to December 2008. We also screened reference lists of articles and contacted the authors and vaccine manufacturers for additional references. We included randomized and nonrandomized studies assessing the anamnestic immune response to the booster of HB vaccine in healthy participants 5 years or more after initial vaccination.

Results: The meta-analysis included 34 studies with 53 intervention groups and 4,479 individuals. The protective antibodies induced by initial vaccination waned over time; however, nonprotected vaccinees who had lost their antibodies to hepatitis B surface antigen (anti-HBs) over time responded strongly to the booster dose. The seroprotection rate of HB vaccine after the primary vaccination was 98.00% [95% confidence interval (CI): 95.32%, 99.52%] after 5 years, 96.88% [95% CI: 94.61%, 98.50%] after 6-10 years, 88.80% [95% CI: 79.84%, 95.08%] after 11-15 years, and 85.12% [95% CI: 82.18%, 88.20%] after 16-20 years.

Conclusions: According to these findings, the protection provided by HB vaccine is dependent on immune memory rather than anti-HBs titer; therefore, recommendations for booster doses should be based on immune memory instead of the persistence of antibody. In addition, a full course of HB vaccination can induce a long-term and strong serologic immunity against hepatitis B virus infection. Nonetheless, the decreasing trend of seroprotection during the first and second decades after immunization indicates that the long-term immunity induced by HB vaccine may diminish over time. This issue raises the possibility of the need for a booster dose, although universal revaccination does not seem necessary during the first and second decades after primary vaccination in healthy individuals with normal immune status who had fully responded to a complete course of the vaccine.

Keywords: Hepatitis B Vaccine, Immunization, Immunologic Memory, Immunity

The protection provided by hepatitis B (HB) vaccine has been well documented (1, 2). Antibody to hepatitis B surface antigen (anti-HBs) concentrations ≥10 mIU/ml are generally considered protective against hepatitis B virus (HBV) infection (1, 3). However, the protective antibodies induced by HB vaccination wane gradually over time and may reach very low or even undetectable levels (4, 5).

Some long-term follow-up studies have indicated that a 3-dose vaccination schedule provides immunity against HBV infection for as long as 15 years (2, 6). In addition, immunologic studies have revealed that HB vaccine induces immunologic memory, so that memory B cells can proliferate, differentiate, and retain the capacity to generate a rapid and vigorous anamnestic immune response upon re-exposure to hepatitis B surface antigen (HBsAg), even if the anti-HBs titer falls below the protective level (7-9). Hence, disappearance of the antibody does not necessarily imply loss of protection. Nonetheless, HBV breakthrough infection and chronic carriage state have been reported in some vaccinees especially in endemic regions (2, 6, 10). Moreover, adults are less likely than infants to demonstrate an anamnestic response as they grow older (7), and the risk of HBV infection increases with sexual and occupational exposure during adulthood (11). In the context of these relatively limited results, the duration of immunity provided by the complete course of the vaccine is unknown because vaccine protection is not parallel to anti-HB titer. Indeed, it is not clear whether a decline in serum anti-HB level indicates the need for a booster dose.

There is a practical approach to determining the duration of protection provided by HB vaccine. In this approach, we assumed that the response to the booster dose mimics the response to the wild virus. Therefore, through measuring the immune response after administration of a booster dose of the vaccine at definite time intervals from the initial vaccination, we indirectly assessed the presence of anamnestic immune response (AIR) and therefore the vaccine's long-term immunogenicity against HBV infection.

Because unnecessary HB revaccination is wasteful, none of the international guidelines recommend that booster doses be administered universally (1, 12-14). Furthermore, the duration of protection provided by HB vaccine is important for public health authorities who have to plan immunization programs and formulate future booster policies. As a result, the seroprotection rate of HB vaccine still requires further investigation (12, 15, 16). We found a few review articles (1, 15-17) but no meta-analysis addressing the booster dose of HB vaccine. In this meta-analysis, we took a practical approach to determine the "seroprotection rate" (SR) of HB vaccine and the need for a booster dose.

Materials and Methods

AIR is typically defined in two ways (8, 9, 18, 19): a) experiencing a four-fold or greater rise in post-booster anti-HBs titer within 2 to 4 weeks of the booster dose administration for participants having detectable antibody or b) developing a post-booster anti-HBs level equal to or greater than 10 mIU/ml within 2 to 4 weeks of the booster dose administration for participants with no detectable antibody. In addition, protected participants are defined as vaccinees having an anti-HBs titer ≥10 mIU/ml, and nonprotected participants are defined as vaccinees having an anti-HBs titer <10 mIU/ml (1, 3).

Criteria for including studies

Types of studies: Both randomized and nonrandomized studies addressing AIR to booster doses of vaccines were included in this meta-analysis. We considered nonrandomized studies, because most studies exploring immune response to booster dose were nonrandomized in design (Fig. 1). We included studies irrespective of randomization, publication status, or language. We excluded short-term trials (fewer than 5 years follow-up from the initial vaccination).

Figure 1. Design of the review for assessing the long-term seroprotection of HB vaccine

            P1: proportion of protected participants;

            P2: proportion of nonprotected participants;

            PAIR: proportion of anamnestic immune response in nonprotected participants.

Types of participants: We limited our investigation to apparently healthy participants, who had intact immune status, no previous HBV infection, and who had already received a complete course of HB vaccine. We excluded those studies whose participants a) were not screened for serologic markers of HBV infection before admission to the study; b) were born to carrier mothers; c) had no clear and reliable vaccination history; d) received an incomplete course of HB vaccine; e) received HB vaccine in fixed combination with other vaccines; f) received HB vaccine plus immunoglobulin; and g) had predisposing factors for immunodeficiency such as HIV or hemodialysis.

Types of intervention: The intervention of interest was administering a booster dose of HB vaccine to already immunized participants to assess the long-term presence (5 years or more) of AIR to the booster dose (Fig. 1). We assessed booster effect irrespective of type, dosage, injection route, and injection site.

Types of primary outcomes: We assessed two types of primary outcomes, including a) the proportion of protected participants at the end of the follow-up period (P1) and b) the proportion of nonprotected participants with AIR to the booster dose (PAIR).

Search methods

Electronic databases: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 3), MEDLINE (Jan 1950 to Dec 2008), EMBASE (Jan 1980 to Dec 2008), and Science Citation Index Expanded (Jan 1945 to Dec 2008).

Other sources: We scanned the reference lists of all included studies for additional references. We also contacted the authors of the included studies as well as vaccine manufacturers for additional unpublished trials. In addition, the following conference databases were searched for unpublished data:

Annual Meeting of the Infectious Diseases Society of America (IDSA), retrieved from htttp://www.idsociety.org ;

European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), retrieved from http://www.escmid.org ; and

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) retrieved from  http://www.icaac.org .

Data collection and analysis

Two authors independently made the decisions on which trials meet the inclusion criteria considered for this review. The two authors were not blinded to the names of the authors of the included studies, the journals, or the results. Any disagreements were resolved through discussion among the authors until a consensus was reached. Excluded trials were listed with the reasons for exclusion.

We extracted data regarding the Data Collection and Abstraction Form. In cases of missing data or need for clarification, the trial authors were contacted.

Three authors assessed the risk of bias in the included studies using a risk-of-bias tool. Any disagreements were resolved through discussion among the authors until a consensus was reached. The studies that had an adequate handling of incomplete outcome data, were free of selective reporting, included an adequate intervention description, had appropriate criteria for participant recruitment, and included an adequate outcome explanation were considered low-bias risk trials. The studies with one or more unclear or inadequate quality component were considered high-bias risk trials.

To handle withdrawals and dropouts in the analysis, we used an available-participant approach, meaning that we included data on only those participants whose results were known, using as a denominator the total number of people who had data recorded for AIR.

Seroprotection rate

Vaccinated individuals having an anti-HBs level ≥10 mIU/ml are generally considered protected (1, 3), whereas vaccinated people with an anti-HBs level <10 mIU/ml may not be protected and are assessed in this review. Seroprotection rate (SR) determines the proportion of protective immunity provided by HB vaccine among vaccinated individuals. SR consists of the proportion of protected participants plus the proportion of nonprotected participants who responded to the booster. SR is calculated by the following formula (20):

SR = [P1 + (P2 × PAIR)] × 100,

where P1 is proportion of protected participants; P2 is proportion of nonprotected participants; and PAIR is the proportion of nonprotected participants with an anamnestic immune response.

Both Review Manager 5 (21) and Stata 9 were used for the data analysis. A meta-analysis was performed to obtain the summary measures P2 and PAIR using a random-effects model with a 95% confidence interval (CI). To explore statistical heterogeneity we used the chi-square (χ2 or Chi2) test at the 10% significance level (P < 0.10). We also used the I2 statistic to quantify inconsistency in results across studies. In addition, a funnel plot was employed for assessing publication bias.

Figure 3. Forest plot of proportion of nonprotected participants (PNP) across different strata.

Figure 4. Forest plot of anamnestic immune response (AIR) to booster dose in nonprotected participants across different strata.

Figure 5. Proportion of protected and nonprotected participants, proportion of anamnestic immune response to booster dose among nonprotected participants, and the seroprotection rate of HB vaccine in different periods after primary vaccination.

Subgroup analysis

To assess the effect of various variables on the seroprotection rate of HB vaccine, we ignored the strata and performed the subgroup analysis of all studies together to enhance sample sizes across different levels of variables to obtain more precise estimates. The variables under investigation included the methodological quality of the studies, types of participants, and types of vaccine.

There were 15 low-risk and 19 high-risk trials among the included studies. The subgroup analysis indicated that SR was 96.08% [95% CI: 93.10% to 98.21%] for the low-risk studies and 94.29% [95% CI: 90.01% to 97.36%] for the high risk studies (P < 0.438).

The age range of participants varied from 5 to over 60 years. Nonetheless, 93% (4,155 out of 4,479) of participants were 5 to 24 years old. Therefore, due to sparse data, it was impossible to perform a subgroup analysis across different age groups.

Of the 53 intervention groups, 42 groups comprised the general population, whereas the remaining 11 intervention groups comprised health care workers (HCWs). The subgroup analysis revealed that SR was 94.74% [95% CI: 91.75% to 97.11%] in the general population, whereas it was 96.83% [95% CI: 93.88% to 98.87%] among HCWs (P < 0.266).

For the primary vaccination, a recombinant vaccine (RV) was used for 32 intervention groups, a plasma-derived vaccine (PDV) was used for 21 groups, and a mixed RV/PDV combination was used for 1 group. The subgroup analysis indicated that SR was 96.72% [95% CI: 94.10% to 98.59%] among RV recipients and 92.11% [95% CI: 86.41% to 96.27%] among PDV recipients (P < 0.104).

HB vaccine had been administered in a 3-dose schedule for 44 intervention groups, in a 4-dose schedule for 7 groups, and in a mixed schedule for the remaining 3 groups. However, the number of subgroups across strata was not enough to perform a subgroup analysis.

Most of the intervention groups (49 out of 53) had received a booster of RV, and 2 groups had received PDV. The type of booster was not specified in the remaining 2 groups; hence, there were not enough data to perform a subgroup-analysis across different types of booster. In addition, participants had received different booster doses for various types of RV, including Engerix-B, Recombivax HB, Genhevac B, Euvax B, and Hevac. Because the antigen contents of recombinant vaccines differ and the recommended vaccine doses vary across products from different manufacturers, assessing the dose-response relationship across intervention groups was not reasonable.

We calculated the fold rise in geometric mean titer (GMT) from the baseline to assess the strength of the immune response to the booster in different strata. GMT rose 2,243-fold in Stratum 1, 284-fold in Stratum 2, 20-fold in Stratum 3, and 112-fold in Stratum 4. Furthermore, to determine the best time to measure GMT after the booster dose, we compared the results of 7 trials in which GMT was measured sequentially 3 times during the first, second, and fourth weeks after the booster dose. GMT increased 18-fold during the first week, reached 512-fold in the second week, and then decreased to 356-fold during the fourth week.

Discussion

We found that the protective anti-HBs induced by initial vaccination waned over time, and thus the proportion of nonprotected vaccinees increased over time. Nonetheless, a considerable proportion of nonprotected participants who had lost anti-HBs over time responded vigorously to the booster dose. Therefore, according to these findings, the protection provided by a complete course of HB vaccine is dependent on immune memory rather than anti-HBs titer.

The observed dynamic of SR by strata is interesting and merits special attention because of its decreasing trend. The SR for HB vaccine was relatively high in the first 5 years after primary vaccination and decreased a little during the first decade. However SR decreased much more during the second decade and reached 85% 16 to 20 years after immunization. Therefore, attention should focus on this decreasing trend, which may indicate a certain fragility of the long-term immunity induced by HB vaccine. This raises the possibility of the need for a booster dose after the second decade, although revaccination does not seem necessary during the first or second decade after primary vaccination.

We developed a wide search strategy to encompass as many studies as possible. We screened 4,699 retrieved references and included 34 eligible studies involving 4,479 participants. Therefore, the amount of studies and the body of evidence identified allowed for a robust conclusion regarding the long-term seroprotection rate of HB vaccine. Although the number of actual participants may have been adequate in Stratum 4, the number of studies may not have been sufficient to confidently address the long-term protection provided by HB vaccine for as long as 16-20 years post initial vaccination. In addition, 93% of the participants aged 5 to 24 years and all of the participants in this review were apparently immunocompetent. Therefore, we cannot confidently generalize the results of this review to adults aged >25 years or to the immunocompromised population.

We calculated the multiplicative rise in GMT from the baseline to assess the strength of the immune response to the booster in different strata. GMT rose 2,243-fold in Stratum 1, 284-fold in Stratum 2, 20-fold in Stratum 3, and 112-fold in Stratum 4. Furthermore, to determine the best time of measuring GMT post booster dose, we compared the results of 7 trials in which GMT was measured sequentially 3 times during the first, second, and fourth weeks after the booster dose. GMT increased 18-fold during the first week, reached 512-fold in the second week, and then decreased to 356-fold during the fourth week.

According to the results of this meta-analysis, GMT increased during the first and second weeks after booster injection and then decreased thereafter. Therefore, the best time for measuring immune response to a booster dose is at the end of second week after the administration of the booster.

Although the amount of included studies seems sufficient, the funnel plot was asymmetric. The methodological quality of the included studies differed, which itself may be an important potential source of funnel plot asymmetry. In addition, the heterogeneity in the results of the included studies may have also led to the funnel plot asymmetry in our review. Moreover, the exclusion of short-term booster studies (those with fewer than 5 years of follow-up) from our meta-analysis may have been another reason for funnel plot asymmetry.

There was evidence of heterogeneity (small P value and large I2 statistic) among the results of the included studies. However, care must be taken in the interpretation of tests of heterogeneity. The importance of the observed value of I2 depends on a) the magnitude and direction of the effects and b) the strength of evidence for heterogeneity (e.g., P value from the Chi2 test) (63). In addition, the Chi2 test has low power when the sample size is small. Inversely, the statistic has high power in detecting a small amount of heterogeneity that may be clinically unimportant when there are many studies in a meta-analysis (63), as was the case in our review. Therefore, we can attribute the observed heterogeneity to many studies being included in the meta-analysis as well as large sample sizes.

In this review, we revealed that the protection provided by HB vaccine is dependent on immune memory, rather than anti-HB titer, and furthermore that the seroprotection rate against HBV infection is sufficient in people who responded to a complete course of the vaccine. Thus, booster doses are unnecessary in immunocompetent persons for at least 20 years after primary vaccination. Our findings are confirmed by other reviews. For instance, one review revealed that protection was independent on antibody titer and indicated that following a complete course of vaccination, booster doses are unnecessary in immunocompetent persons (17). Another review found that immune response to the vaccine after 10 years was powerful in vaccinees whose antibody titer decreased to below the protective level (16). A third review revealed that immune memory lasted for at least 15 years in immunocompetent individuals and emphasized that there are no data to support the need for booster doses of HB vaccine in immunocompetent individuals who have responded to a primary course (15). Finally, Mast et al. claimed that substantial evidence suggests that adults who respond to HB vaccination are protected from chronic HBV infection for at least 20 years, even if vaccinees lack detectable anti-HBs levels at the time of exposure (1).

Conclusions

We found that the protection provided by HB vaccine is dependent on immune memory rather than anti-HB titer; hence, recommendations for booster doses should be based on immune memory instead of persistence of the antibody. We also revealed that, following a full course of immunization, HB vaccine will induce a long-term and strong serologic immunity against HBV infection during the first and second decades after primary vaccination. However, SR decreased during the first decade and then decreased even faster in the second decade. This trend may indicate a degree of frailty in the long-term immunity induced by HB vaccine and raises the possibility of the need for a booster dose after the second decade. Still, universal revaccination does not seem necessary during the first and second decades after primary vaccination in healthy individuals with intact immune status who had fully responded to a complete course of the vaccine.

Acknowledgements

We thank Dimitrinka Nikolova, Review Group Coordinator of the Cochrane Hepato-Biliary Group, who was involved in the formulation, supervision, and improvement of the protocol, as well as Sarah Louise Klingenberg and Kate Whitfield, Trials Search Coordinators of the Cochrane Hepato-Biliary Group, for designing the search strategies. We also thank Tahany Awad from Denmark and Joseph Luis Mathew from India, peer reviewers of the protocol, for their very worthwhile recommendations. We wish to acknowledge Christian Gluud, Coordinating Editor of the Cochrane Hepato-Biliary Group for editing the protocol. Finally, we thank Raheleh Kia-shemshaki for translating the Chinese article.

This study was supported by the Department of Epidemiology and Biostatistics in the School of Public Health at Tehran University of Medical Sciences (TUMS), Tehran, Iran.

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