Booster dose vaccination for preventing hepatitis B

  • Review
  • Intervention

Authors

  • Jalal Poorolajal,

    Corresponding author
    1. School of Public Health, Hamadan University of Medical Sciences, Modeling of Noncommunicable Diseases Research Center, Department of Epidemiology, Hamadan, Hamadan, Iran
    • Jalal Poorolajal, Modeling of Noncommunicable Diseases Research Center, Department of Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Shahid Fahmideh Ave, Hamadan, Hamadan, 6517838695, Iran. poorolajal@umsha.ac.ir. poorolajal@yahoo.com.

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  • Elham Hooshmand

    1. School of Public Health, Hamadan University of Medical Sciences, Department of Epidemiology, Hamadan, Iran
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Abstract

Background

Antibodies against hepatitis B surface antigen (HBsAg) wane over time following hepatitis B immunisation; hence, it is unclear whether people vaccinated in three-dose or four-dose schedules of the hepatitis B vaccine are still immune when the hepatitis B surface antibody (anti-HBs) level in their body is undetectable, or lower than the level usually considered protective. This question may potentially be answered indirectly by measuring the anamnestic immune response to a booster dose of vaccine. The term 'booster' (or revaccination) refers to an additional dose of hepatitis B vaccine (HBV) given some time post-primary vaccination to induce immune memory and improve protection against hepatitis B virus (HBV) infection.

Objectives

To assess the benefits and harms of booster dose hepatitis B vaccination, more than five years after the primary vaccination, for preventing HBV infection in healthy individuals previously vaccinated with the hepatitis B vaccine, and with hepatitis B surface antibody (anti-HBs) levels below 10 mIU/mL.

Search methods

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, conference databases, and reference lists of articles to January 2016. We also contacted authors of articles. In addition, we searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials (May 2016).

Selection criteria

Randomised clinical trials addressing anamnestic immune response to a booster dose of hepatitis B vaccine, more than five years after the primary vaccination, in apparently healthy participants, vaccinated in a three-dose or four-dose schedule of the hepatitis B vaccine during the primary vaccination, without receiving an additional dose or immunoglobulin.

Data collection and analysis

Both review authors decided if the identified studies met the inclusion criteria or not. Primary outcomes included the proportion of participants with anamnestic immune response in non-protected participants and signs of HBV infection. Secondary outcomes were the proportion of participants that developed local and systemic adverse events following a booster dose injection. We planned to report the weighted proportion with 95% confidence intervals (CIs).

Main results

There were no eligible randomised clinical trials fulfilling the inclusion criteria of this review.

Authors' conclusions

We were unable to include any randomised clinical trials on the topic; only randomised clinical trials will be able to provide an answer as to whether a booster dose vaccination is able to protect against hepatitis B infection.

Plain language summary

Booster dose for preventing hepatitis B infection

Background
Antibodies against hepatitis B surface antigen (HBsAg) wane over time following hepatitis B immunisation; hence, it is unclear whether people vaccinated in 3-dose or 4-dose schedules of the hepatitis B vaccine during their primary vaccination are still immune when the hepatitis B surface antibody (anti-HBs) level in their body is undetectable, or lower than the level usually considered protective. This question may potentially be answered indirectly by measuring the anamnestic immune response to a booster dose of vaccine given to people previously immunised with the hepatitis B vaccine.

Aim
The authors selected to assess the benefits and harms of a booster dose of hepatitis B vaccine, more than five years after the primary vaccination.

Searches
Electronic searches were performed up until January 2016.

Selection criteria
Randomised clinical trials addressing immune response (i.e., the way your body recognises and defends itself against bacteria, viruses, and substances that appear foreign and harmful to the body) to a booster dose of hepatitis B vaccine, more than five years after the primary vaccination in apparently healthy participants, vaccinated in a three-dose or four-dose schedule of hepatitis B vaccine during their primary vaccination, without receiving an additional dose of the hepatitis B vaccine or immunoglobulin.

Main results and conclusions
We were unable to find any eligible randomised clinical trials to include in this review. There is no scientific evidence, based on randomised clinical trials, to support or reject the need for booster doses of hepatitis B vaccine in healthy individuals with normal immune status. We need evidence, based on randomised clinical trials, to formulate future booster vaccination policies.

Laienverständliche Zusammenfassung

Auffrischimpfung zum Schutz vor Hepatitis B-Infektion

Hintergrund
Die Anzahl an Antikörpern gegen das Hepatitis B-Oberflächenantigen (HBsAg) nimmt nach einer Hepatitis B-Impfung mit der Zeit wieder ab. Bei Personen, die ihre Erstimpfung einst mit 3 oder 4 Teildosen Hepatitis B-Impfstoff erhalten haben, ist daher unklar, ob der Impfschutz auch dann noch besteht, wenn Hepatitis B-Oberflächenantikörper (anti-HBs) im Körper nicht mehr nachweisbar sind oder wenn der Spiegel an anti-HBs niedriger liegt, als man es üblicherweise für einen Impfschutz für nötig hält. Diese Frage könnte möglicherweise indirekt beantwortet werden, indem man bei Personen, die früher bereits gegen Hepatitis B geimpft worden waren, die anamnetische Immunantwort auf eine Auffrischimpfung misst.

Ziel
Die Autoren beschlossen Nutzen und Schaden einer Hepatitis B-Auffrischimpfung nach mehr als fünf Jahren nach der Erstimpfung zu untersuchen.

Suchen
Die elektronischen Suche wurde bis Januar 2016 durchgeführt.

Auswahlkriterien
Randomisierte klinische Studien, die die Immunantwort (d.h. die Weise, in der der Körper Bakterien, Viren und andere Substanzen, die ihm fremd und gefährlich erscheinen, erkennt und sich dagegen wehrt) auf Hepatitis B-Auffrischimpfungen nach mehr als fünf Jahren nach der Erstimpfung in scheinbar gesunden Teilnehmern untersuchten, die einst 3 oder 4 Teildosen Hepatitis B-Impfstoff zur Erstimpfung erhalten hatten, ohne weitere spätere Dosen von Hepatitis B-Impfstoff oder Immunglobulin.

Hauptergebnisse und Schlussfolgerungen
Wir konnten keine geeigneten randomisierten klinischen Studien finden um sie in diesen Review einzuschließen. Es gibt keine auf randomisierten klinischen Studien basierende wissenschaftliche Evidenz, um die Notwendigkeit von Auffrischimpfungen bei gesunden Individuen mit normalem Immunstatus zu unterstützen oder zu verwerfen. Wir brauchen auf randomisierten klinischen Studien basiernde Evidenz um zukünftige Strategien zur Auffrischimpfung zu erarbeiten.

Anmerkungen zur Übersetzung

V. Labonté, freigegeben durch Cochrane Deutschland.

Background

Description of the condition

The protection provided by the hepatitis B vaccine has been well documented (Chen 2005; McMahon 2005; Mast 2006; Poorolajal 2009a). Hepatitis B surface antibody (anti-HBs) concentrations equal to or greater than 10 mIU/mL are generally considered protective against hepatitis B virus (HBV) infection (WHO 2002; Mast 2006). However, the protective antibodies induced by the hepatitis B vaccine wane gradually over time and may reach very low or even undetectable levels (Wainwright 1997; Dentinger 2005). It is not known if anti-HBs concentrations below 10 mIU/mL offer protection against HBV infection. Furthermore, we do not know the exact benefits and harms of a booster dose vaccination in people previously vaccinated against the HBV. The term 'booster' (or revaccination) refers to an additional dose of hepatitis B vaccine given some time post-primary vaccination to induce immune memory and improve protection against HBV infection.

Description of the intervention

The evidence based on several long-term follow-up studies has indicated that the protection provided by three or four doses of monovalent hepatitis B vaccine during the primary vaccination persists for at least two decades (Poorolajal 2009b; Poorolajal 2010a). In addition, immunologic studies have revealed that hepatitis B 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 titre falls below 10 mIU/mL (Watson 2001; van der Sande 2007). Hence, disappearance of the antibody may not necessarily imply loss of protection against hepatitis B infection. Nonetheless, a HBV breakthrough infection, detected by the presence of the hepatitis B core antibody (anti-HBc) in the blood, and chronic HBV carriage, detected by the presence of HBsAg in the blood, are reported in some vaccinees, especially in endemic regions (Hadler 1986; Liao 1999; McMahon 2005). Moreover, adults are less likely than infants to demonstrate an anamnestic response of their immune reaction to the HBV or hepatitis B vaccine as they grow older (Samandari 2007), and the risk of HBV infection increases by sexual and occupational exposures during adulthood (Whittle 2002). In the context of these relatively limited results, the duration of immunity provided by a complete course of primary vaccine is unknown because vaccine protection may not be parallel to the anti-HBs titre. Indeed, it is not clear whether a decline in serum anti-HBs level implies the need for a booster dose of the vaccine or not.

How the intervention might work

When anti-HBs levels fall to low or undetectable levels, a HBV vaccine booster dose may raise antibody levels, leading to increased protection against subclinical and clinical HBV infection. Subclinical infection can be detected by measuring the occurrence of anti-HBc. Clinical infection can be measured by detecting clinical symptoms and verifying the diagnosis of acute hepatitis B infection using hepatitis B serology.

A practical approach in determining the duration of protection provided by hepatitis B vaccine could be if we assume that the response to a booster dose of hepatitis B vaccine mimics the response to hepatitis B wild virus infection. Accordingly, the serologic response to a booster dose may be considered as a surrogate marker for assessing the presence of protection against the wild virus. Therefore, through measuring the immune response to a booster dose of vaccine in definite post-primary vaccination periods, we can assess the presence of anamnestic immune response, and potentially assess the long-term immunity induced by hepatitis B vaccine against HBV infection.

Why it is important to do this review

As unnecessary hepatitis B revaccination is wasteful, none of the international guidelines recommend booster doses to be applied universally (WHO 2003; John 2005; Puro 2005; Mast 2006). Furthermore, duration of protection provided by the hepatitis B vaccine is important for public health authorities who have to plan immunisation programmes and formulate future booster vaccination policies. Hence, protective immunity of the vaccine still requires further investigation (European Consensus Group 2000; FitzSimons 2005; John 2005; Poorolajal 2010b). We found some review articles (European Consensus Group 2000; Banatvala 2003; Chen 2005; FitzSimons 2005; Lee 2006; Mast 2006), and two meta-analyses that address the anamnestic immune response to a booster dose of hepatitis B vaccine (Poorolajal 2009b; Poorolajal 2010a). However, these meta-analyses were based on the results of observational studies rather than randomised clinical trials. This raises the risks of confounding and bias. In this systematic review, we aim to determine the long-term protection of hepatitis B vaccine and the need for a hepatitis B vaccine booster dose, using the results of randomised clinical trials.

Objectives

To assess the benefits and harms of booster dose hepatitis B vaccination, more than five years after the primary vaccination, for preventing hepatitis B virus (HBV) infection in healthy individuals previously vaccinated with the hepatitis B vaccine, and with hepatitis B surface antibody levels (anti-HBs) below 10 mIU/mL.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include randomised clinical trials addressing response to a hepatitis B vaccine booster dose in non-protected vaccinees, i.e., vaccinees with hepatitis B surface antibody (anti-HBs) level below 10 mIU/mL (Figure 1). We planned to include randomised clinical trials, irrespective of blinding, publication status, or language.

Figure 1.

NPV: non-protected vaccinees (with anti-HBs less than 10 mIU/mL)
AIR: anamnestic immune response
* Positive: number with anti-HBs at or above 10 mIU/mL
** Negative: number with anti-HBs below 10 mIU/mL

For our review, we planned to consider randomised clinical trials only with more than five years follow-up after the primary vaccination because several observational follow-up studies indicated that none of the vaccinated participants became hepatitis B surface antigen (HBsAg) positive during the first five years following their primary hepatitis B vaccination (Wainwright 1989; Lai 1993; Mintai 1993; Zhang 1993; Goh 1995; Joshi 1995; Yuen 1999; But 2008; Gilca 2009). In addition, the World Health Organization (WHO) stated that the duration of vaccine-induced immunity was uncertain, but it was definitely long-term, i.e., more than 15 years (WHO 2002). Accordingly, we planned to exclude short-term randomised clinical trials, i.e., trials with equal to or less than five years interval between the initial vaccination and the booster dose (Appendix 1).

Types of participants

We planned to include those apparently healthy, non-protected participants with intact immune status, without previous serological signs of hepatitis B virus (HBV) infection (i.e., positive regarding HBsAg and/or hepatitis B core antibody (anti-HBc)), and who have already received vaccination against hepatitis B in a three-dose or four-dose schedule more than five years earlier during their primary vaccination. Non-protected participants were those vaccinees whose anti-HBs concentrations in the blood fell to below 10 mIU/mL (WHO 2002; Mast 2006).

We planned to exclude randomised clinical trials with participants who: a) were not screened for serologic markers of HBV infection (HBsAg and anti-HBc) before admission into the trial; b) have no clear vaccination history; c) were immunised in a less than three-dose vaccination schedule during their primary vaccination; d) received hepatitis B vaccine plus immunoglobulin; and e) had predisposing factors for immunodeficiency, such as HIV-positive or haemodialysis (Appendix 1).

Types of interventions

The planned intervention of interest was administration of a booster dose of hepatitis B vaccine versus placebo or no intervention to already immunised participants to assess long-term (more than five years) presence of anamnestic immune response to booster dose versus placebo (Figure 1). The term 'booster' refers to an additional dose of hepatitis B vaccine given some time post-primary vaccination to induce immune memory and improve protection against HBV infection. We planned to assess the booster effect, irrespective of type of hepatitis B vaccine, dosage, route, or site of injection (Appendix 1).

Types of outcome measures

Primary outcomes
  • Any sign or symptom of hepatitis B virus (HBV) infection, either acute or chronic hepatitis B infection, or the development of hepatitis B core antibody (anti-HBc) in serum or plasma.

  • Cirrhosis or hepatocellular carcinoma caused or associated with chronic hepatitis B infection, and mortality due to hepatitis B infection.

  • Proportion of participants that developed serious adverse events after the booster dose injection, including fever, headache, malaise, irritability, rash, nausea, myalgia, arthralgia, or any other systemic adverse events (WHO 2001). Serious adverse events were defined as any outward medical occurrence that was life-threatening, resulted in death, or persistent or significant disability, or any medical event, which may have jeopardised the patient, or required intervention to prevent it (ICH-GCP 1997).

Secondary outcomes
  • Quality of life.

  • Non-serious adverse events.

  • Proportion of participants that developed local adverse events at the booster dose injection site, including pain, redness, swellings, or any other local adverse events (WHO 2001).

The dichotomous outcome of interest was the proportion with anamnestic immune response in non-protected participants and signs of HBV infection. The continuous outcome of interest was the intensity of anamnestic immune response in non-protected participants. The intensity of immune response is the amount of fold rise in geometric mean titre post-booster compared to pre-booster administration. Anamnestic immune response to booster doses is defined in the following two ways (Watson 2001; Williams 2003; Yuen 2004; van der Sande 2007):

  • Proportion with a four-fold or greater rise in the post-booster anti-HBs titre within two to four weeks of the booster dose administration in participants having any measurable antibody in the pre-booster blood sample.

  • Proportion with development of post-booster anti-HBs level equal to or greater than 10 mIU/mL within two to four weeks of the booster dose administration in participants with no detectable antibody in the pre-booster blood sample.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2016), the Cochrane Central Register of Controlled Trials (Wiley) (CENTRAL; 2015, Issue 12), MEDLINE (Ovid SP), EMBASE (Ovid SP), and Science Citation Index Expanded (Web of Science) (Royle 2003), until January 2016. The search strategies with the time spans of the searches are described in Appendix 2.

We searched ClinicalTrials.gov (clinicaltrials.gov/) and the WHO International Clinical Trial Registry Platform (www.who.int/ictrp) for ongoing trials (May 2016).

Searching other resources

We scanned the reference lists of all retrieved studies and pertinent reviews for additional references. We contacted authors of retrieved studies as well as vaccine manufacturers for additional unpublished randomised trials. We searched the following conference databases for unpublished data until December 2014.

  • Annual Meeting of the Infectious Diseases Society of America (IDSA); available from www.idsociety.org.

  • European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); available from www.escmid.org.

  • Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); available from www.icaac.org.

Data collection and analysis

Selection of studies

We (JP and EH) read the retrieved publications separately in order to identify the trials that would meet the inclusion criteria of this review (Appendix 1). We were not blinded to the authors' names, journals, or results. We resolved any disagreements through discussion. We had to exclude all identified publications, and we have provided the reasons for exclusion in the Characteristics of excluded studies tables.

Data extraction and management

We entered the extracted data regarding the 'Data collection and abstraction form' in electronic data sheets (Appendix 3). In case of missing data or need for clarification, we contacted study authors.

Assessment of risk of bias in included studies

We intended to assess the risk of bias of the included studies using the ‘Risk of bias’ tool recommended by Cochrane (Higgins 2011) (Appendix 4). It was to be done independently by the review authors (JP and EH) and any disagreements were to be resolved through discussion among the review authors until consensus was reached. If information was not available in the published trial, we planned to contact any of the authors of the trial in order to assess the trials correctly.

The trials judged at 'low' risk of bias in the domains of sequence generation, allocation concealment, blinding of participants and caregivers, blinding of outcome assessors, handling of incomplete outcome data, selective outcome reporting, vested interests, and without other bias risks were to be considered trials at low risk of bias.

The trials judged to be at 'high' or 'unclear' risk of bias regarding any of the domains above were to be considered trials with high risk of bias. Any disagreements were to be resolved through discussion among the review authors, until consensus was reached.

Measures of treatment effect

The effect measure of choice for dichotomous outcomes was the risk ratio (RR), and the effect measure of choice for continuous outcomes was the mean difference (MD). We planned to report all estimates with 95% confidence intervals (CIs).

Dealing with missing data

To handle withdrawals and dropouts in the analysis, we planned to use the 'available data approach' (Higgins 2011), as well as include data on only those participants whose results were known, using as a denominator the total number of people who had data recorded for anamnestic immune response (Higgins 2011).

Assessment of heterogeneity

We planned to consider the Chi2 test at the 10% significance level (P < 0.10) to explore statistical heterogeneity. We also planned to quantify inconsistency across results of the trials using the I2 statistic (Higgins 2003), and to estimate the between-studies variance by using the Tau2 statistic (Higgins 2011).

Assessment of reporting biases

We planned to create a funnel plot to assess publication bias and other bias risks.

Data synthesis

We planned to use Review Manager 5 for data analysis (RevMan 2014). We planned to analyse data using both a random-effects model (DerSimonian 1986) and a fixed-effect model (DeMets 1987) with 95% CI. We planned to report both analyses in case there were discrepancies regarding the significance of the intervention effects; otherwise, the results of the fixed-effect model only. We planned to put most weight on the most conservative finding in our interpretation (Jakobsen 2014).

Trial Sequential Analysis

We intended to conduct Trial Sequential Analysis (Thorlund 2011; TSA 2011) to control the risk of random error and prevent premature statements of superiority of the experimental or control intervention (Wetterslev 2008). We intended to conduct the Trial Sequential Analysis for primary and secondary outcomes with a type I error of 2.5%, type II error of 20% (80% power), and adjusted for diversity among the included trials (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). We assumed an event proportion as observed in the control group and an anticipated intervention effect of 20% relative risk reduction.

Subgroup analysis and investigation of heterogeneity

We planned to assess anamnestic immune response to booster dose for the following subgroups.

  • Various periods: every five years from initial vaccination.

  • Various methodological quality: trials with low risk of bias compared to trials with high risk of bias.

  • Various endemic regions: low endemicity (prevalence of HBV infection less than 2%) compared to intermediate endemicity (prevalence of HBV infection 2% to 7%) and high endemicity (prevalence of HBV infection more than 7%).

  • Various age groups: every 10 years.

  • Various participants: apparently healthy participants compared to healthcare workers, or intravenous drug abusers, or sex partners.

  • Various vaccination schedules of the primary vaccination: three-dose compared to four-dose.

  • Various vaccine or booster types: recombinant vaccine compared to plasma derived vaccine.

  • Various booster dosages: 5 μg compared to 10 μg.

  • Various injection sites: deltoid or thigh compared to gluteus.

  • Various injection routes: intramuscular compared to intradermal.

Sensitivity analysis

We planned to conduct a sensitivity analysis to assess the impact of dropouts and withdrawals for whom no outcome data were obtained, based on the following two scenarios (Gamble 2005).

  • 'Best-case scenario': assuming all missing participants responded to the booster dose in the booster arm and failed to respond in the control arm, using the total number of participants as the denominator.

  • 'Worst-case scenario': assuming all missing participants failed to respond to the booster dose in the booster arm and responded in the control arm, using the total number of participants as the denominator.

A true worst-case scenario (from the perspective of the use of a booster) would be to consider all lost cases in the booster arm to be failures and all lost cases in the control arm to be successes. A best-case scenario would be the opposite. Any estimate that remains significant in both of these scenarios is robust.

'Summary of findings' tables

We planned to summarise the evidence in 'Summary of findings' tables using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) criteria (GRADEpro). We planned to assess five factors referring to limitations in the study design and implementation of included studies that suggest the quality of the evidence; risk of bias - indirectness of evidence (population, intervention, control, outcomes); unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses); imprecision of results (wide CIs and as evaluated with our Trial Sequential Analyses) (Jakobsen 2014); and a high probability of publication bias. If we include studies in future updates, we will define the levels of evidence as 'high', 'moderate', 'low', or 'very low'. These grades are defined as follows.

  • High certainty: this research provides a very good indication of the likely effect; the likelihood that the effect will be substantially different is low.

  • Moderate certainty: this research provides a good indication of the likely effect; the likelihood that the effect will be substantially different is moderate.

  • Low certainty: this research provides some indication of the likely effect; however, the likelihood that it will be substantially different is high.

  • Very low certainty: this research does not provide a reliable indication of the likely effect; the likelihood that the effect will be substantially different is very high.

Results

Description of studies

Results of the search

We developed a search strategy to include randomised clinical trials exploring anamnestic immune response to booster doses of hepatitis B vaccine. Up to January 2016, we retrieved 660 references through searching electronic databases, 118 references through checking reference lists, and 296 references through checking relevant clinical trial registries. Of 12 references we considered potentially eligible after screening, we did not consider any eligible to be included in the review, and we excluded these references from the review (Figure 2) (Characteristics of excluded studies).

Figure 2.

Study flow diagram.

Included studies

We did not find any randomised clinical trials to meet the objectives and the inclusion criteria of the review.

Excluded studies

We excluded 12 studies from the review because: four had no control (placebo or no intervention) group; four assessed immune response to booster dose administered before five years from initial vaccination; three did not exclude protected vaccinees from non-protected vaccinees; and one compared modified regimens of hepatitis B vaccine with the recommended regimen (Characteristics of excluded studies).

Risk of bias in included studies

There were no eligible trials to be included in the review and hence to be assessed for risk of bias.

Effects of interventions

There were no eligible trials to be included in the review and hence to be assessed for the effects of intervention.

Discussion

Summary of main results

According to the objectives of this review, we intended to assess anamnestic immune response to the hepatitis B vaccine booster dose in vaccinees after five years from the initial hepatitis B vaccination with hepatitis B surface antibody (anti-HBs) levels below 10 mIU/mL. We restricted our systematic review to randomised clinical trials only. We did not identify any randomised trials to fulfil the inclusion criteria of this review, and hence, we could not meet the objectives of our review. However, in our search process for identification of randomised trials, as well as through previous research done by us (Poorolajal 2009b; Poorolajal 2010a), we identified several non-randomised studies which addressed anamnestic immune response to a booster dose of hepatitis B vaccine in non-protected vaccinees, without considering any control group.

Quality of the evidence

We developed a wide search strategy to encompass as many studies as possible. Although we retrieved 660 references, we could not find any eligible randomised trials to include in the review and therefore we could not assess any quality of evidence.

Potential biases in the review process

For this review, we found no randomised clinical trials or controlled clinical studies.

Agreements and disagreements with other studies or reviews

Non-randomised studies

All studies, found through our previous non-Cochrane research, included a total of 3551 participants (Poorolajal 2009b; Poorolajal 2010a). These studies assessed anamnestic immune response to a booster dose five to 20 years post-initial vaccination.

We divided the participants into four strata based on duration from the last primary vaccination (Poorolajal 2009b; Poorolajal 2010a). Stratum 1 included studies that investigated anamnestic immune response to a booster dose five years post-initial vaccination; stratum 2 included studies that assessed anamnestic immune response to a booster dose six to 10 years post-initial vaccination; stratum 3 included studies that assessed anamnestic immune response to a booster dose 11 to 15 years post-initial vaccination; and stratum 4 included studies that assessed anamnestic immune response to a booster dose 16 to 20 years post-initial vaccination. Stratum 1 included 12 studies with 480 participants; stratum 2 included 27 studies with 1405 participants; stratum 3 included 12 studies with 1883 participants; and stratum 4 included two studies with 711 participants.

We conducted a meta-analysis on non-randomised studies to estimate the overall anamnestic immune response to a booster dose five to 20 years after initial vaccination. Based on the results of this meta-analysis, the response proportion to a booster dose was 92% (95% CI 88% to 96%) after five years; 92% (95% CI 89% to 95%) after six to 10 years; 80% (95% CI 72% to 88%) after 11 to 15 years; and 76% (95% CI 73% to 80%) after 16 to 20 years (Poorolajal 2009b). However, we should remember that considering the response to a booster dose of hepatitis B vaccine for assessing the presence of protection against the wild virus is only an unvalidated surrogate marker (Gluud 2007). Therefore, no response to booster dose does not necessarily mean susceptibility to live virus infection. And, on the other hand, one does not know if response to a booster dose means effective prevention against infection, although this is likely.

The results of previously published meta-analyses revealed the fact that although anti-HBs concentrations equal to or greater than 10 mIU/mL are generally considered protective against hepatitis B virus (HBV) infection (WHO 2002; Mast 2006), the opposite of this does not seem correct. In other words, anti-HBs concentrations less than 10 mIU/mL or absence of anamnestic immune response cannot be considered absence of immunity.

Another meta-analysis was conducted on non-randomised studies to estimate the duration of protection provided by the hepatitis B vaccine (Poorolajal 2010a). The results indicated that the overall incidence rate of HBV breakthrough infection five to 20 years after initial vaccination was 0.007 (95% CI 0.005 to 0.010) with a variation among studies from 0 to 0.094. Available data do not allow us to exclude an increased risk for infection with time since vaccination. We concluded that the protection provided by three or four doses of hepatitis B vaccine could persist for at least two decades (Poorolajal 2010a).

Randomised clinical trials

We found three randomised trials addressing the effect of various types of hepatitis B booster dose. However, these trials did not meet our inclusion criteria because they did not have a placebo control group or assessed the effect of booster dose before five years from the initial vaccination. The results of these trials are described below.

A randomised multicentre, open-label clinical trial was conducted in Spain to assess the anamnestic immune response to a hepatitis B booster dose among four to eight year-old children after initial hepatitis B vaccination. A total of 1478 children were enrolled in this multicentre trial and stratified into three cohorts (A, B, and C) from 77 primary care centres in Spain and one site in Canada. Participants in cohort A included 751 participants who initially were vaccinated with Recombivax. Participants in cohort B included 707 participants who were initially vaccinated with Engerix-B. And cohort C included 20 participants who received no primary hepatitis B vaccine series. The participants were randomised to receive the hepatitis B booster dose as follows. In cohort A, 374 participants received a booster dose of minipool HBV (mpHBV) (group 1) and 375 participants received Engerix-B (group 2). In cohort B, 349 participants received mpHBV (group 3) and 352 participants received Engerix-B (group 4). All 20 participants in cohort C received a dose of mpHBV (group 5). Some participants were lost during the follow-up period. Before the booster dose vaccination, 15.9% to 51.2% of participants had hepatitis B antibody concentrations equal to or greater than 10 mIU/mL. One month after the booster dose vaccination, 91.6% to 97.3% of the participants had antibody concentrations equal to or greater than 10 mIU/mL. The authors concluded that measuring anti-HBs post-booster dose may be an indicator of long-term post-vaccination protection against hepatitis B infection even if the pre-booster anti-HBs level is undetectable (Diez-Domingo 2010).

A randomised open-label trial was conducted in Italy to investigate the response to a booster dose of monovalent hepatitis B vaccine in 410 children immunised with three doses of either Hexavac (n = 201) or Infanrix-Hexa (n = 209) during infancy. Children were randomised into two groups to receive a single booster dose of either HBVaxPro (n = 62) or Engerix-B (n = 348). Anti-HBs concentrations were measured before and one month after the booster dose. One month post-booster: 91% (86% to 95%) of children in the Hexavac group and 98% (95% to 99%) in the Infanrix-Hexa group had anti-HBs concentrations equal to or greater than 10 mIU/mL (Zanettia 2012).

A randomised double-blind, placebo-controlled field trial was conducted to assess the efficacy of a booster dose of hepatitis B vaccine in 104 primary school children with a good response to initial vaccination three years after the primary vaccination. The participants were randomised to receive either hepatitis B booster dose (53 participants) or placebo (51 participants). At the end of the six-year follow-up (three years after the revaccination), the proportion of anti-HBs positive in the revaccinated group was 88% versus 69% in the control group (P < 0.01) (Zhuang 1998).

Authors' conclusions

Implications for practice

There were no eligible randomised clinical trials to include in the review. There is no scientific evidence based on randomised clinical trials to support or refute the need for a booster dose of hepatitis B vaccine in healthy individuals, with normal immune status, who had fully responded to a complete course of the vaccine.

Implications for research

The clinical consequences of offering a booster dose to healthy people with hepatitis B surface antibody (anti-HBs) levels below 10 mIU/mL more than five years after initial hepatitis B vaccination are not known. In principle, therefore, we need to conduct such randomised clinical trials. However, such trials will need to be very large in order to be meaningful, and accordingly expensive. Such costs have to be weighed against a policy where one offers a booster vaccination without knowing the clinical consequences. This review did not aim to include immunocompromised persons such as HIV-infected individuals, haemodialysis patients, and persons receiving chemotherapy, so we cannot make any implications for research for these groups. Hence, the need for a booster dose in these groups also has to be investigated. These trials ought to be conducted according to the SPIRIT statement and reported according to the CONSORT statement.

Acknowledgements

We thank previous authors of the first version of this review - Mahmoodi M, Haghdoost A, Majdzadeh R, Nasseri-Moghaddam S, Ghalichi L, Fotouhi A - for their dedicated work (Poorolajal 2010b).

We thank Dimitrinka Nikolova who was involved in the formulation, supervision, and improvement of the Cochrane protocol and review as well as Sarah Louise Klingenberg for designing the search strategies. We also thank Kate Whitfield for sending us papers on trials.

Peer Reviewer: Ronald L Koretz, USA.
Contact Editors: Gennaro D'Amico, Italy; Christian Gluud, Denmark.

Cochrane Review Group funding acknowledgement: The Danish State is the largest single funder of the Cochrane Hepato-Biliary Group through its investment in the Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark.

Disclaimer: The views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or the Copenhagen Trial Unit.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Inclusion-exclusion criteria

CriteriaIncludedExcluded
Types of studies
Has the trial assessed anamnestic immune response to booster dose?YesNo
Have the participants been randomised to booster hepatitis B vaccination versus placebo or no vaccination?YesNo
Types of participants
Were they apparently healthy participants, with intact immune status, without previous hepatitis B virus infection?YesNo
Were they free of predisposing factors for immunodeficiency?YesNo
Were they screened for serologic markers of hepatitis B virus infection before admission into the trial?YesNo
Have the participants already received either a 3-dose or a 4-dose schedule of hepatitis B vaccine?YesNo
Was their vaccination history clear and reliable?YesNo
Did they receive a monovalent hepatitis B vaccine not in fixed combination with other vaccines?YesNo
Did they receive hepatitis B vaccine without immunoglobulin?YesNo
Types of interventions
Was the administered booster dose a monovalent vaccine of either recombinant vaccine (RV) or plasma derived vaccine (PDV)?YesNo
Primary outcomes
Was the anamnestic immune response to booster dose of hepatitis B vaccine versus placebo investigated?YesNo

Appendix 2. Search strategies

DatabaseTime of searchesSearch terms
The Cochrane Hepato-Biliary Group Controlled Trials RegisterJanuary 2016boost* AND (vaccin* OR immuni* OR engerix-B OR euvax-B OR recombivax OR twinrix) AND hepatitis B
The Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley)Issue 12 of 12, 2015

#1 MeSH descriptor: [Immunization, Secondary] explode all trees

#2 boost*

#3 #1 or #2

#4 MeSH descriptor: [Hepatitis B Vaccines] explode all trees

#5 vaccin* or immuni* or engerix-B or euvax-B or recombivax or twinrix

#6 #4 or #5

#7 MeSH descriptor: [Hepatitis B] explode all trees

#8 hepatitis B

#9 #7 or #8

#10 #3 and #6 and #9

MEDLINE (Ovid SP)1946 to January 2016

1. exp Immunization, Secondary/

2. boost*.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]

3. 1 or 2

4. exp Hepatitis B Vaccines/

5. (vaccin* or immuni* or engerix-B or euvax-B or recombivax or twinrix).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]

6. 4 or 5

7. exp Hepatitis B/

8. hepatitis B.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]

9. 8 or 7

10. 6 and 3 and 9

11. (random* or blind* or placebo* or meta-analysis).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]

12. 11 and 10

EMBASE (Ovid SP)1974 to January 2016

1. boost*.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

2. exp Hepatitis B Vaccine/

3. (vaccin* or immuni* or engerix-B or euvax-B or recombivax or twinrix).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

4. 3 or 2

5. exp Hepatitis B/

6. hepatitis B.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

7. 6 or 5

8. 4 and 1 and 7

9. (random* or blind* or placebo* or meta-analysis).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

10. 8 and 9

Science Citation Index Expanded (Web of Science)1900 to January 2016

#6 #5 AND #4

#5 TS=(random* or blind* or placebo* or meta-analysis)

#4 #3 AND #2 AND #1

#3 TS=(hepatitis B)

#2 TS=(vaccin* OR immuni* OR engerix-B OR euvax-B OR recombivax OR twinrix)

#1 TS=(boost*)

Appendix 3. Data collection and abstraction form

RowDataResults
BoosterPlacebo
11st author 
2Date of publication 
3Design of clinical trialRandomised clinical trial 
Quasi-randomised study 
4Follow-up time from last vaccination (year) 
5EndemicityHigh 
Intermediate 
Low 
6ParticipantsGeneral population 
Healthcare workers 
Intravenous (IV) drug abusers 
Sex partners 
Others 
7Mean age (year)  
8Vaccine schedule3-dose 
4-dose 
9Initial vaccine typeRecombinant vaccine (RV) 
Plasma derived vaccine (PDV)? 
10Proportion with response to initial vaccination (%)  
11Booster typeRecombinant vaccine (RV)  
Plasma derived vaccine (PDV)?  
12Booster dosage (mcg)  
13Injection siteDeltoid 
Thigh 
Gluteus 
14Injection routeIM 
ID 
SD 
15Sample size  
16Dropouts  
17Anamnestic immune response (AIR)  
18Proportion of anamnestic immune response (PAIR)  
19Before intervention (booster)GMT (mIU/mL)  
95% CI of GMT  
201 week after intervention (booster)GMT (mIU/mLl)  
95% CI of GMT  
212 weeks after booster dose (booster)GMT (mIU/mL)  
95% CI of GMT  
223 weeks after intervention (booster)GMT (mIU/mL)  
95% CI of GMT  
234 weeks after intervention (booster)GMT (mIU/mL)  
95% CI of GMT  
242 months after intervention (booster)GMT (mIU/mL)  
95% CI of GMT  
251 year after intervention (booster)GMT (mIU/mL)  
95% CI of GMT  
26Adverse events of boosterLocalPain  
Tenderness  
Redness  
Swelling  
Other  
SystemicFever  
Headache  
Malaise  
Irritability  
Rash  
Nausea  
Myalgia  
Arthralgia  
Other  

Appendix 4. Assessment of risk of bias of the included studies

Random sequence generation

Criteria for a judgement of ‘low risk’ of bias

The investigators describe a random component in the sequence generation process from the following.

  • Referring to a random number table

  • Using a computer random number generator

  • Coin tossing

  • Shuffling cards or envelopes

  • Throwing dice

  • Drawing of lots

  • Minimisation

Criteria for the judgement of ‘high risk’ of bias

The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, such as the following.

  • Sequence generated by odd or even date of birth

  • Sequence generated by some rule based on date (or day) of admission

  • Sequence generated by some rule based on hospital or clinic record number

  • Allocation by judgement of the clinician

  • Allocation by preference of the participant

  • Allocation based on the results of a laboratory test or a series of tests

  • Allocation by availability of the intervention

Criteria for the judgement of ‘unclear risk’ of bias

Insufficient information about the sequence generation process to permit judgement of ‘low risk’ or ‘high risk’

Allocation concealment

Criteria for a judgement of ‘low risk’ of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation.

  • Central allocation (including telephone, web-based and pharmacy-controlled randomisation)

  • Sequentially numbered drug containers of identical appearance

  • Sequentially numbered, opaque, sealed envelopes

Criteria for the judgement of ‘high risk’ of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on the following.

  • Using an open random allocation schedule (e.g., a list of random numbers)

  • Assignment envelopes were used without appropriate safeguards (e.g., if envelopes were unsealed or non­opaque or not sequentially numbered)

  • Alternation or rotation

  • Date of birth

  • Case record number

  • Any other explicitly unconcealed procedure

Criteria for the judgement of ‘unclear risk’ of bias

Insufficient information to permit judgement of ‘low risk’ or ‘high risk’. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement – for example, if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque, and sealed

Blinding of participants and personnel

Criteria for a judgement of ‘low risk’ of bias

Any one of the following.

  • No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding

  • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken

Criteria for the judgement of ‘high risk’ of bias

Any one of the following.

  • No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding

  • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding

Criteria for the judgement of ‘unclear risk’ of bias

Any one of the following.

  • Insufficient information to permit judgement of ‘low risk’ or ‘high risk’

  • The study did not address this outcome

Blinding of outcome assessment

Criteria for a judgement of ‘low risk’ of bias

Any one of the following.

  • No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding

  • Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

Criteria for the judgement of ‘high risk’ of bias

Any one of the following.

  • No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding

  • Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding

Criteria for the judgement of ‘unclear risk’ of bias

Any one of the following.

  • Insufficient information to permit judgement of ‘low risk’ or ‘high risk’

  • The study did not address this outcome

Incomplete outcome data

Criteria for a judgement of ‘low risk’ of bias

Any one of the following.

  • No missing outcome data

  • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias)

  • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate

  • For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size

  • Missing data have been imputed using appropriate methods

Criteria for the judgement of ‘high risk’ of bias

Any one of the following.

  • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate

  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size

  • ‘As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation

  • Potentially inappropriate application of simple imputation

Criteria for the judgement of ‘unclear risk’ of bias

Any one of the following.

  • Insufficient reporting of attrition/exclusions to permit judgement of ‘low risk’ or ‘high risk’ (e.g., number randomised not stated, no reasons for missing data provided)

  • The study did not address this outcome

Selective reporting

Criteria for a judgement of ‘low risk’ of bias

Any of the following.

  • The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way

  • The study protocol is not available but it is clear that the published reports include all expected outcomes (anamnestic immune response and signs of hepatitis B virus infection), including those that were prespecified (convincing text of this nature may be uncommon)

Criteria for the judgement of ‘high risk’ of bias

Any one of the following.

  • Not all of the study’s prespecified primary outcomes have been reported

  • One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g., subscales) that were not prespecified

  • One or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect)

  • One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis

  • The study report fails to include results for a key outcome that would be expected to have been reported for such a study

Criteria for the judgement of ‘unclear risk’ of bias

Insufficient information to permit judgement of ‘low risk’ or ‘high risk’. It is likely that the majority of studies will fall into this category

For a trial to be classified as a trial with low risk of bias, it must be judged at low risk of bias in all domains. If this is not the case, the trial will be classified as a trial at high risk of bias

What's new

DateEventDescription
4 April 2016New citation required but conclusions have not changedWe could identify no randomised clinical trials for inclusion in the review until the very end of its resubmission for publication. This is why, in the future, the review will be updated only if such trials are identified.
4 April 2016New search has been performedThe review has been updated following the latest Cochrane requirements for review preparation. There is also a change in the author team.

Contributions of authors

Jalal Poorolajal (JP): developed and wrote the protocol, and was responsible for the reference searching, article retrieval, study inclusion and exclusion, data extraction, assessment of risk of bias in included studies, data analysis, interpretation of results, and writing of the review.

Elham Hooshmand (EH) was responsible for the reference searching, article retrieval, and study inclusion and exclusion.

Declarations of interest

Jalal Poorolajal declares no conflicts of interest.
Elham Hooshmand declares no conflicts of interest.

Sources of support

Internal sources

  • UMSHA, Hamadan, Iran.

    Department of Epidemiology and Biostatistics, School of Public Health, Hamadan Univesity of Medical Science (UMSHA)

External sources

  • No sources of support supplied

Differences between protocol and review

We expanded the review protocol outcomes before we started on the review update. In addition, we expanded the methods of our review protocol with Trial Sequential Analysis and Summary of Findings. We updated the bias risk domains.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Cassidy 2001Comparing modified regimens of hepatitis B vaccine with the recommended regimen
Chan 1991Did not exclude protected vaccinees from non-protected vaccinees
Diez-Domingo 2010Assessing immune response to booster dose before five years from initial vaccination
Gilca 2013No control (placebo or no intervention) group
Teoharov 2013No control (placebo or no intervention) group
Trivello 1995Did not exclude protected vaccinees from non-protected vaccinees
van der Sande 2007Did not exclude protected vaccinees from non-protected vaccinees
Williams 2001No control (placebo or no intervention) group
Wu 2010Assessing immune response to booster dose before five years from initial vaccination
Yao 2011No control (placebo or no intervention) group
Zanettia 2012Assessing immune response to booster dose before five years from initial vaccination
Zhuang 1998Assessing immune response to booster dose before five years from initial vaccination

Ancillary