Booster dose vaccination for preventing hepatitis B

  • Review
  • Intervention

Authors


Abstract

Background

Antibodies against hepatitis B surface antigen (HBs) wane over time after vaccination for hepatitis B (HB); hence, the duration of protection provided by the vaccine is still unknown but may be evaluated indirectly by measuring the anamnestic immune response to booster doses of vaccine.

Objectives

To assess the benefits and harms of booster dose hepatitis B vaccination for preventing HB infection.

Search methods

We searched The Cochrane Hepato-biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 4, 2010) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, conference databases, and reference lists of articles to May 2010. We also contacted authors of articles and manufacturers.

Selection criteria

Randomised clinical trials addressing anamnestic immune response to booster of HB vaccine five years or more after primary vaccination in apparently healthy participants, vaccinated in a 3-dose or 4-dose schedules of HB vaccine without receiving additional dose or immunoglobulin.

Data collection and analysis

Two authors made the decisions if the identified publications on studies met the inclusion criteria or not. Primary outcome measures included the proportion with anamnestic immune response in non-protected participants and signs of hepatitis B virus infection. Secondary outcomes were the proportion with local and systemic adverse event events developed following booster dose injection. Weighted proportion were planned to be reported with 95% confidence intervals.

Main results

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

Authors' conclusions

We were unable to identify randomised clinical trials on the topic. We need randomised clinical trials to formulate future booster policies for preventing hepatitis B infection.

Resumen

Antecedentes

Vacunación con dosis de refuerzo para la prevención de la hepatitis B

Los anticuerpos contra el antígeno de superficie de la hepatitis B (HBs) disminuyen con el tiempo tras la vacunación contra la hepatitis B (HB); por lo tanto, la duración de la protección proporcionada por la vacuna aún se desconoce, pero se puede evaluar indirectamente al medir la respuesta inmunitaria anamnésica a las dosis de refuerzo de la vacuna.

Objetivos

Evaluar los beneficios y los daños de la vacunación con dosis de refuerzo contra la hepatitis B para la prevención de la infección por HB.

Estrategia de búsqueda

Se hicieron búsquedas en el Registro de Ensayos Controlados del Grupo Cochrane Hepatobiliar (Cochrane Hepatobiliary Group), Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) (número 4, 2010) en The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, bases de datos de congresos y en listas de referencias de artículos hasta mayo 2010. También se estableció contacto con los autores de los artículos y con los fabricantes.

Criterios de selección

Ensayos clínicos aleatorios que abordan la respuesta inmunitaria anamnésica de la dosis de refuerzo de la vacuna contra la HB cinco años o más después de la vacunación primaria en participantes aparentemente sanos, vacunados en regímenes de tres o cuatro dosis de la vacuna, sin recibir dosis adicionales ni inmunoglobulina.

Obtención y análisis de los datos

Dos revisores decidieron si las publicaciones identificadas en los estudios cumplían los criterios de inclusión. Las medidas de resultado primarias incluyeron la proporción con respuesta inmunitaria anamnésica en participantes sin protección y signos de infección por virus de hepatitis B. Los resultados secundarios fueron la proporción que presentó eventos adversos locales y sistémicos después de la inyección con dosis de refuerzo. Se planificó informar la proporción ponderada con los intervalos de confianza del 95%.

Resultados principales

No había ensayos clínicos aleatorios elegibles que cumplieron los criterios de inclusión de esta revisión.

Conclusiones de los autores

No fue posible identificar ensayos clínicos aleatorios sobre el tema. Se necesitan ensayos clínicos aleatorios para formular las políticas de refuerzo futuras para prevenir la infección por hepatitis B.

Traducción

Traducción realizada por el Centro Cochrane Iberoamericano

摘要

背景

追加注射疫苗對預防B型肝炎的效果

在接受B型肝炎(hepatitis B,HB)疫苗之後,對抗B型肝炎表面抗原(hepatitis B surface antigen,HBs)的抗體會隨著時間減弱;雖然目前仍不清楚疫苗可以提供保護的期間,但可能可藉由測量追加注射疫苗的再生抗體免疫反應(anamnestic immune response),以間接的方式來評估。

目標

評估追加注射疫苗對預防B型肝炎的效果與傷害。

搜尋策略

我們搜尋了The Cochrane Hepatobiliary Group Controlled Trials Register、在The Cochrane Library的Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 4, 2010)、MEDLINE、EMBASE、Science Citation Index Expanded 、研討會資料庫、以及至2010年5月的文獻參考清單,我們同時也與文獻的作者與廠商接觸。

選擇標準

研究有關明顯的健康參與者注射疫苗後超過(含)5年 及初次依預定時間表注射3或4劑B型肝炎疫苗 而未曾接受追加劑量或免疫球蛋白者,當其追加注射疫苗後再生抗體免疫反應的隨機對照試驗。

資料收集與分析

搜尋出來的文獻,由二位作者決定其研究是否符合納入的標準。主要結果的測量,包括未受保護的參與者的再生抗體免疫反應,以及B型肝炎病毒感染的症狀。次要結果的測量,則包括追加注射疫苗後發生局部或全身性不良事件(adverse events)的比例。計畫將加權比例(weighted proportion)和95% 信賴區間(95% confidence intervals)同時報告。

主要結論

目前找不到完全符合本研究納入條件的隨機臨床試驗。

作者結論

目前無法找到符合本主題的隨機臨床試驗,所以,我們需要有相關的隨機臨床試驗,才能進一步制定出追加疫苗注射對預防B型肝炎感染的政策。

翻譯人

本摘要由門諾醫院鄭珮文翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

以追加注射疫苗來預防B型肝炎: 對抗B型肝炎表面抗原(antiHBs)的抗體,會在接受B型肝炎疫苗之後隨著時間而減弱。因此,究竟B型肝炎疫苗提供的保護期有多長,目前仍是未知的。但是,疫苗產生的免疫記憶(immune memory)可以間接的以測量追加注射疫苗所產生的再生抗體免疫反應來評估。目前沒有符合的隨機臨床試驗可以納入評估,沒有科學證據支持或反駁有正常免疫反應的健康個人是否需要追加注射B型肝炎疫苗。我們需要更多隨機臨床試驗的證據,來制定未來追加注射疫苗的政策。

Résumé scientifique

Vaccination avec une dose de rappel en prévention de l'hépatite B

Contexte

Les anticorps contre l'antigène de surface de l'hépatite B (HB) diminuent au fil du temps après la vaccination contre l'hépatite B (HB) ; la durée de la protection conférée par le vaccin est donc encore indéterminée mais elle peut être évaluée indirectement en mesurant la réponse immunitaire anamnestique aux doses de vaccin de rappel.

Objectifs

Évaluer les bénéfices et les risques de la vaccination contre l'hépatite B avec une dose de rappel en prévention de l'infection par l'hépatite B.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans Le registre des essais contrôlés du groupe Cochrane sur les affections hépato-biliaires, le Registre Cochrane des essais contrôlés (CENTRAL) (numéro 4, 2010) dans The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, les bases de données de conférences, et les listes bibliographiques des articles jusqu'au mois de mai 2010. Nous avons aussi contacté des auteurs d'articles et des fabricants.

Critères de sélection

Les essais cliniques randomisés abordant la réponse immunitaire anamnestique à une dose de rappel de vaccin contre l'hépatite B cinq ans ou plus longtemps après la première vaccination chez des participants apparemment en bonne santé, vaccinés selon des schémas posologiques à 3 administrations ou 4 administrations de vaccin contre l'hépatite B sans recevoir de dose supplémentaire ou d'immunoglobuline.

Recueil et analyse des données

Deux auteurs étaient chargés de déterminer si les publications des études identifiées répondaient ou non aux critères d'inclusion. Les principaux critères de jugement mesurés comprenaient la proportion des participants non protégés produisant une réponse immunitaire anamnestique et les signes d'infection causée par le virus de l'hépatite B. Les critères de jugement secondaires étaient la proportion de sujets signalant des événements indésirables systémiques et locaux développés suite à l'injection de la dose de rappel. Il était prévu que les proportions pondérées soient rapportées avec des intervalles de confiance (IC) à 95 %.

Résultats principaux

Aucun essai clinique randomisé éligible ne répondait aux critères d'inclusion de la présente revue.

Conclusions des auteurs

Nous ne sommes pas parvenus à identifier des essais cliniques randomisés portant sur ce sujet. Nous avons besoin d'essais cliniques randomisés pour formuler les futures politiques de vaccination de rappel en prévention de l'infection par l'hépatite B.

Plain language summary

Booster dose for preventing hepatitis B infection

Antibodies against hepatitis B surface antigen (anti-HBs) wane over time after vaccination for hepatitis B, hence the duration of protection provided by HB vaccine is still unknown. However, the presence of immune memory can be evaluated indirectly by measuring the anamnestic immune response to a booster dose of vaccine.

There were no eligible randomised clinical trials to be included in the review. There is no scientific evidence to support or reject the need for booster doses of HB vaccine in healthy individuals with normal immune status. We need evidence, based on randomised clinical trials to formulate future booster policies.

Résumé simplifié

Dose de rappel en prévention de l'infection par l'hépatite B

Les anticorps contre l'antigène de surface de l'hépatite B (anti-HB) diminuent au fil du temps après la vaccination contre l'hépatite B ; la durée de la protection conférée par le vaccin HB est donc encore indéterminée. Toutefois, la présence de la mémoire immunitaire peut être évaluée indirectement en mesurant la réponse immunitaire anamnestique à une dose de vaccin de rappel.

Nous n'avons trouvé aucun essai clinique randomisé éligible pour l'inclusion dans la présente revue. Il n'existe aucune preuve scientifique permettant de corroborer ou réfuter le nécessité d'administrer des doses de rappel de vaccin contre l'hépatite B à des individus en bonne santé ayant un statut immunitaire normal. Nous avons besoin de preuves, fondées sur des essais cliniques randomisés pour formuler les futures politiques de vaccination de rappel.

Notes de traduction

Traduit par: French Cochrane Centre 2nd May, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Summary of findings(Explanation)

Summary of findings for the main comparison. Summary findings of non-RCTs
  1. - No data

    PRRIV: protective response rate to Initial vaccination.

    PAIR: proportion of anamnestic immune response to booster dose in non-protected vaccinees.

    GMTpre: geometric mean titre pre-booster dose.

    GMTpost: geometric mean titre post-booster dose.

    * the sample size of some studies are very small because most of the participants in these studies were protected vaccinees and were excluded from the analysis.

    ** Frequency weighted average.

StratumStudyFollow-up (yr)EndemicityParticipantsAge group (yr)VaccineBoosterSample size*PRRIVPAIRGMTpreGMTpostFold rise
1Belloni 20005HypoHealthy5RV-51100%1.00---
Bucher 19945HypoHCWs40.4PDVRV47Unknown0.89---
Bucher 19945HypoHCWs40.9PDVPDV49Unknown0.80---
Da Villa 19965HyperHealthy5MixedRV27Unknown0.96---
Dahifar 20085IntermediateHealthy6.5RVRV4100%1.00---
Duval 20055HypoHealthy15.1RVRV38100%0.92---
Duval 20055HypoHealthy15.1RVRV50100%0.96---
Gilca 20085HypoHealthy15.5RVRV36100%0.94---
Milne 1992a5HypoHealthy6.1PDVRV55Unknown0.82---
Milne 1992b5HyperHealthy18RVRV8100%1.00---
Petersen 20045HyperHealthy5.2RVRV71Unknown0.850.071572243
Trivello 19925HypoHCWsadultsRVRV21100%0.192.44844.93346
Trivello 19925HypoHCWsadultsRVRV78100%0.171458.47458
Williams 20035HyperHealthy5.3RVRV4490%0.93---
Total-5-----579-0.78**--1190**
2Floreani 20046IntermediateHCWs31.4RVRV11Unknown0.45---
Floreani 20046IntermediateHCWs28.8PDVRV7Unknown1.00---
Li 19986HyperHealthy6-7PDVPDV65Unknown0.77---
Peces 20016IntermediateHCWs RVRV1Unknown1.00---
Samandari 20076HyperHealthy5.9RVRV116Unknown0.97---
Seto 20026HypoHealthy6.1RVRV34100%1.00---
Trivello 19956HypoHCWs29.8PDVRV40100%0.88---
Trivello 19956HypoHCWs30.8PDVRV99100%0.92---
Davidson 19867HypoHCWs43PDVRV16Unknown0.81---
Li 19967HyperHealthy8-11PDVPDV2694%1.000.127.8278
Petersen 20047HyperHealthy7.4RVRV21100%0.860.24126525
Petersen 20047HyperHealthy7.5RVRV14100%1.000.2463263
Petersen 20048HyperHealthy8.1RVRV63Unknown0.950.071572243
Milne 19949HyperHealthy11-12RVRV17Unknown0.942158.479
Petersen 20049HyperHealthy9.1PDVRV25Unknown0.520.0734486
Williams 20019HyperHCWs46.7RVRV13100%1.000.96633658
Williams 20019HyperHCWs46.7RVRV15100%1.006.831920281
Williams 20039HyperHealthy9.25PDVRV25Unknown0.88---
Chadha 200010IntermediateHCWs37.3RVRV1080%0.80---
Da Villa 199610HyperHealthy10PDVRV147Unknown0.96---
Durlach 200310HypoHCWs44.3RVRV15100%0.80---
Gilca 200810HypoHealthy20.3RVRV42100%1.00---
Petersen 200410HyperHealthy10.4PDVRV29Unknown0.690.0734486
Saffar 200410IntermediateHealthy10.7RVRV57Unknown0.953.84166.7643
Saffar 200410IntermediateHealthy10.7RVRV52Unknown0.883.84130.934
Saffar 200410IntermediateHealthy10.7RVRV56Unknown0.793.84103.227
Zanetti 200510HypoHealthy10.9RVRV342Unknown0.9732.1885.628
Zanetti 200510HypoHealthy21.8RVRV48Unknown0.96234.81715.17
Total-------1406-0.92**--277**
3Gabbuti 200711HypoHealthy23RVRV12100%0.92124.12790.422
Xueliang 200011HyperHealthy16-20PDVRV27Unknown0.782.122612
Petersen 200412HyperHealthy12.6PDVRV12100%0.670.241146
Samandari 200712HyperHealthy11.8RVRV118Unknown0.81---
Lu 2008a13HyperHealthy13.14RV-522Unknown0.74---
Watson 200113HypoHealthy14-23RVRV3Unknown1.00---
Watson 200113HypoHealthy43-67RVRV2Unknown1.00---
Samandari 200714HyperHealthy14PDVRV58Unknown0.60---
Hammitt 200715HyperHealthy14.6RVRV37100%0.621.422.716
Lu 200415HyperHealthy15PDVRV49Unknown0.96---
Lu 2008b15HyperHealthy15-17PDVRV872Unknown0.71---
van der Sande 200715HyperHealthy14.9PDVRV143Unknown0.95---
Total-------1855-0.75**--20**
4Wang 200716HyperHealthy15.9PDVRV386Unknown0.771.2662.750
Su 200720HyperHealthy18.7PDVRV139Unknown0.500.055.15103
Su 200720HyperHealthy18.7PDVRV58Unknown0.910.32167.79524
Su 200720HyperHealthy18.7PDVRV119Unknown0.973.54443.95125
Total-------702-0.76**--112**

Summary of findings 2 AIR to booster dose in non-protected vaccinees

Summary of findings 2. AIR to booster dose in non-protected vaccinees
  1. PAIR: proportion of anamnestic immune response in non-protected vaccinees.

StratumNo. of studiesNo. of groupsNo. of participantsWeighted PAIR [95% CI]
111145790.78 [0.75, 0.80]
2182814060.92 [0.91, 0.92]
3101218550.75 [0.74, 0.75]
4227020.76 [0.75, 0.77]

Summary of findings 3 GMT fold rise post booster

Summary of findings 3. GMT fold rise post booster
  1. GMT: geometric mean titre.

StratumNo. of studiesNo. of groupsNo. of participantsWeighted GMT fold-rise
1231701189.9 [1055.3, 1324.6]
2614763276.9 [233.5, 320.3]
3448819.7 [17.4, 22.0]
424702112.4 [102.9, 121.8]

Summary of findings 4 Sequential GMT comparison

Summary of findings 4. Sequential GMT comparison
  1. GMT: geometric mean titre.

TrialNo. of participantsGMT at 1st weekGMT at 2nd weekGMT at 4th week
Dentico 2002168.918.222.8
Samandari 2007743.22829.8
Dentico 20021616.63329.5
Samandari 20071384.6148145
Dentico 20021626.8260.9262.2
Samandari 2007166221070653
Dentico 200216162.91321.21358.7
Weighted average [95% CI]44218.02 [15.27, 20.78]511.88 [465.97, 557.79]356.07 [325.11, 387.03]

Summary of findings 5 Adverse events

Summary of findings 5. Adverse events
  1. Total sample size for assessing adverse events was 1525.

Local eventsFrequency
Pain19
Tenderness0
Redness3
Swelling2
Other1
Systemic eventsFrequency
Fever2
Headache1
Malaise0
Irritability0
Rash0
Nausea2
Myalgia1
Arthralgia0
Other0

Background

Description of the condition

The protection provided by hepatitis B vaccine has been well documented (Chen 2005; McMahon 2005; Mast 2006). Antibody to hepatitis B surface antigen (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 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 may offer protection against hepatitis B virus infection. Furthermore, we do not know the exact benefits and harms of a booster dose vaccination in such persons.

Description of the intervention

Some long-term follow-up studies have indicated that a three-dose vaccination schedule provides immunity against HBV infection for as long as 15 years (Liao 1999; McMahon 2005). In addition, immunologic studies have revealed that hepatitis B vaccine induce 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; Samandari 2007; van der Sande 2007). Hence, disappearance of antibody may not necessarily imply loss of protection. Nonetheless, HBV breakthrough infection, detected by presence of antibody to hepatitis B core antigen (anti-HBc) in the blood, and chronic hepatitis B virus carriage, detected by 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 hepatitis B virus 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 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 possible need for a booster dose of the vaccine.

How the intervention might work

There is a practical approach to determine the duration of protection provided by hepatitis B vaccine. In this approach, we assume that the response to a booster dose of HB vaccine mimics the response to hepatitis B wild virus. Therefore, through measuring the immune response to a booster dose of vaccine in definite periods post primary vaccination, we can assess the presence of anamnestic immune response and potentially assess the long-term immunity induced by hepatitis B vaccine against infection.

Why it is important to do this review

Since 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 hepatitis B vaccine is important for public health authorities who have to plan the immunisation programs and formulate future booster policies. Hence, protective immunity of the vaccine still requires further investigations (European Consensus Group 2000; FitzSimons 2005; John 2005). We found a few review articles (European Consensus Group 2000; Banatvala 2003; Chen 2005; FitzSimons 2005; Lee 2006; Mast 2006) and two meta-analyses (Poorolajal 2009; Poorolajal 2010) that addressed the anamnestic immune response to booster dose of hepatitis B vaccine. However, these meta-analyses were based on the results of non-randomised studies. In this systematic review, we considered an approach to determine long-term protection provided by hepatitis B vaccine and the need for hepatitis B vaccine booster dose based on the results of randomised clinical trials.

Objectives

To assess the benefits and harms of booster dose hepatitis B vaccination for preventing hepatitis B infection in previously hepatitis B vaccinated healthy individuals with anti-hepatitis B level under 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, ie, vaccinees with anti-HBs level under 10 mIU/mL (Figure 1). We planned to include 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 follow-up studies indicated that none of the vaccinated participants became HBsAg positive during the first five years post primary vaccination (Wainwright 1989; Lai 1993; Mintai 1993; Zhang 1993; Goh 1995; Joshi 1995; Yuen 1999; Chadha 2000; Durlach 2003; But 2008; Gilca 2008). In addition, the World Health Organization (WHO) stated that the duration of vaccine-induced immunity was uncertain, but it was definitely long-term, ie, more than 15 years (WHO 2002). Accordingly, we planned to exclude short-term randomised clinical trials, ie, trials with less than five years trials 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 HBV infection (ie, HBsAg positive or anti-HBc positive and both), and who have already received vaccination against hepatitis B in a three-dose or four-dose schedule. Non-protected participants were those vaccinees whose anti-HBs concentrations decreased to less than 10 mIU/ml (WHO 2002; Mast 2006).

We planned to exclude studies whose participants: 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; 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 (five years or more) 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 booster effect, irrespective of type, dosage, route, or site of injection (Appendix 1).

Types of outcome measures

Primary outcomes

The dichotomous outcome of interest was the proportion with anamnestic immune response (AIR) in non-protected participants (PAIR) and signs of hepatitis B virus infection. The continuous outcome of interest was intensity of AIR in non-protected participants (IAIR).The intensity of immune response is the amount of fold rise in geometric mean titre (GMT) post-booster compared to pre-booster administration. Anamnestic immune response to booster doses is defined in 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.

Signs of hepatitis B virus infection are to be assessed by:

  • Any sign of hepatitis B virus infection, either acute or chronic hepatitis B infection, or hepatitis B core antigen (anti-HBc).

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

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

  • Proportion with systemic adverse events developed after the booster dose injection, including fever, headache, malaise, irritability, rash, nausea, myalgia, arthralgia, or any other systemic adverse events (WHO 2001).

Search methods for identification of studies

Electronic searches

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 4 2010) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003) until May 2010. The search strategies with the time span of the searches are described in Appendix 2.

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. The following conference databases were searched for unpublished data until June 2010:

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

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

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

Data collection and analysis

Selection of studies

Two authors (JP and LG) read the retrieved publications in separate in order to identify the trials that would meet the inclusion criteria of this review (Appendix 1). The authors were not blinded to the authors' names of the publications, journals, and results. Any disagreements were resolved through discussion among the review authors. All identified publications were on studies that had to be excluded and the reasons for exclusion were provided.

Data extraction and management

The extracted data regarding the 'Data Collection and Abstraction Form' (Appendix 3) were entered in the electronic data sheet. In cases of missing data or need for clarification, study authors were contacted.

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 Collaboration (Higgins 2009) (Appendix 4). It was to be done independently by three authors (JP, AF, and LG) (Appendix 4) and any disagreements were to be resolved through discussion among the 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 with low risk of bias in the domains: sequence generation, allocation concealment, blinding, handling of incomplete outcome data, selective reporting, baseline imbalance, and without other bias risks, were to be considered 'low-bias risk trials'.

The trials judged to be with high or uncertain risk of bias were to be considered 'trials with high risk of bias'. Any disagreements were to be resolved through discussion among the authors, until consensus was reached.

Measures of treatment effect

The effect measure of choice for dichotomous outcome was risk ratio (RR), and the effect measure of choice for continuous outcome was mean difference (MD). All estimates were reported with 95% confidence interval (CI).

Dealing with missing data

To handle withdrawals and drop-outs in the analysis we planned to use 'available-participant approach' 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 2009).

Assessment of heterogeneity

We planned to consider the chi-squared test at the 10% significance level (P less than 0.10) to explore statistical heterogeneity. We also planned to quantify inconsistency across results of the trials using I2 statistic (Higgins 2003) and to estimate the between-studies variance by using tau-squared (τ2 or tau2) statistic (Higgins 2009).

Assessment of reporting biases

We planned to consider the funnel plot to assess publication bias and other bias risks.

Data synthesis

We planned to use both Review Manager 5 (RevMan 2008) and Stata statistical program (version 9) (Stata 9) for data analysis. 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.

Subgroup analysis and investigation of heterogeneity

We planned to assess anamnestic immune response (AIR) 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 health-care workers, or intravenous drug abusers, or sex partners.

  • Various vaccination schedules of the primary vaccination: 3-dose compared to 4-dose.

  • Various vaccine or booster types: recombinant vaccine (RV) compared to plasma derived vaccine (PDV).

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

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

  • Various injection routes: intramuscular (IM) compared to intradermal (ID).

Sensitivity analysis

We planned to conduct 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.

Results

Description of studies

Results of the search

We developed a search strategy to include randomised clinical trials exploring anamnestic immune response (AIR) to booster doses of hepatitis B vaccine. Up to May 2010 we retrieved 3742 references; 1251 references through searching electronic databases, 2467 references through checking reference lists, and 24 references through personal contact with authors of publications, or searching conference databases. Of 53 references considered potentially eligible after screening, none was eligible to be included in the review; 48 studies were excluded from the review (Characteristics of excluded studies), and five studies are awaiting classification (Characteristics of studies awaiting classification) because of inaccessibility to full text or inaccessibility to authors for clarification.

Included studies

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

Excluded studies

Forty eight studies were excluded from the review (Characteristics of excluded studies). These studies were excluded because of the following reasons: 39 (81%) were non-randomised studies; 3 (6%) were randomised trials comparing different doses or types of vaccine without considering a control group; 3 (6%) were non-randomised trials comparing different doses or types of vaccine without random assignment; 2 (4%) were randomised clinical trials, which investigated anamnestic immune response to a booster dose during the first five years from last vaccination; and 1 (2%) was a randomised clinical trial, which explored AIR to booster dose in both protected and non-protected vaccinees simultaneously.

Risk of bias in included studies

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

Effects of interventions

See: Summary of findings for the main comparison Summary findings of non-RCTs; Summary of findings 2 AIR to booster dose in non-protected vaccinees; Summary of findings 3 GMT fold rise post booster; Summary of findings 4 Sequential GMT comparison; Summary of findings 5 Adverse events

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

Discussion

Summary of main results

According to the objectives of this review, we intended to assess AIR to hepatitis B vaccine booster dose in non-protected vaccinees after more than five years from the initial hepatitis B vaccination. We restricted our systematic review to randomised clinical trials only. We identified no randomised trials to meet the objectives and to fulfil the inclusion criteria of this review. However, in our search process for identification of randomised trials we identified 35 non-randomised studies, which addressed AIR to a booster dose of HB vaccine in non-protected vaccinees, without considering any control group (Poorolajal 2010). We review this study below.

Non-randomised studies
Of 35 studies, 34 studies were published in English and one in Chinese. Thirty-four studies were published as full papers, and one study was published as a poster presentation (Lu 2008a). Some studies had included more than one intervention group. The parallel intervention groups in the same study varied by booster dosage, route, and site of injection, or vaccination schedule or age. Hence, the 35 studies included in total 58 intervention groups with 4,542 participants (Summary of findings for the main comparison). We considered each intervention group as a separate study for analysis.

We divided the 58 intervention groups into 4 strata based on duration from the last primary vaccination. Stratum 1 included studies that investigated AIR to booster dose five years post initial vaccination; stratum 2 included studies that assessed AIR to booster dose 6 to 10 years post initial vaccination; stratum 3 included studies that assessed AIR to booster dose 11 to 15 years post initial vaccination; and stratum 4 included studies that assessed AIR to booster dose 16 to 20 years post initial vaccination.

Stratum 1 included 11 studies having 14 intervention groups with 579 participants; stratum 2 included 18 studies having 28 intervention groups with 1406 participants; stratum 3 included 10 studies having 12 intervention groups with 1855 participants; and stratum 4 included 2 studies having 4 intervention groups with 702 participants.

Anamnestic immune response to booster dose
Weighted proportion of anamnestic immune response (PAIR) to booster dose in non-protected participants was 0.78 (95% CI 0.75 to 0.80) in stratum 1; 0.92 (95% CI 0.91 to 0.92) in stratum 2; 0.75 (95% CI 0.74 to 0.75) in stratum 3; and 0.76 (95% CI 0.75 to 0.77) in stratum 4 (Summary of findings 2). The remaining participants did not respond to booster dose or responded weakly (i.e., less than a four-fold rise in the post-booster anti-HBs titre).

These results 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), but opposite of this in not correct. In other words, anti-HBs concentrations less than10 mIU/ml cannot be considered absence of immunity. In fact, protection against HBV infection should be evaluated through measuring anamnestic immune response to booster dose rather than anit-HBs titre.

Geometric mean titre (GMT)
We also calculated the fold rise in geometric mean titre (GMT) from the baseline to assess the strength of AIR to booster dose in non-protected participants across different strata. GMT was reported in 14 studies (including 25 intervention groups). In most intervention groups, GMT was measured at least twice or more during the first, second, and fourth week after the booster dose, and in some studies two months and one year later. We considered the greatest post booster GMT for comparison to the baseline before the booster dose. The GMT fold rise from the baseline was 1189.9 (95% CI 1055.3 to 1324.6) for stratum 1; 276.9 (95% CI 233.5 to 320.3) for stratum 2; 19.7 (95% CI 17.4 to 22.0) for stratum 3; and 112.4 (95% CI 102.9 to 121.8) for stratum 4 (Summary of findings 3).

Best time for measuring GMT post booster injection
In addition, to determine the best time for measuring GMT post booster dose administration, we compared the results of seven studies in which GMT was measured sequentially three times during the first, second, and fourth week after the booster dose. GMT increased from 18.02 (95% CI 15.27, 20.78) on the first week to 511.88 (95% CI 465.97, 557.79) on the second week, and then decreased to 356.07 (95% CI 325.11, 387.03) on the fourth week (Summary of findings 4).

Serological clinical signs of hepatitis B infection
No signs of hepatitis B virus infection, either acute or chronic hepatitis B infection or antibody to hepatitis B surface antigen (anti-HBs) or antibody to hepatitis B core antigen (anti-HBc) were reported. Cirrhosis or hepatocellular carcinoma caused or associated with chronic hepatitis B infection were not reported either.

Adverse events of booster dose
Adverse events subsequent to booster dose were reported in 13 studies with the total sample size of 1252 participants. A recombinant vaccine (RV) was administered as a booster dose into deltoid muscle in all these studies. Pain, the most prevalent local adverse event, was reported in 15 participants. Other local adverse events were reported rarely, including redness in three participants and swelling in two other participants. Systemic adverse events occurred less than local events. Fever and nausea were reported in two participants each, and headache and myalgia in one participant each (Summary of findings 5).

Quality of the evidence

We developed a wide search strategy to encompass as many studies as possible. However, there was no eligible randomised trial to be included in the review, although 4542 references were retrieved. Hence, the amount of studies and body of evidence investigated in this review does not allow us to conclude of the benefits or harms of booster vaccination.

Potential biases in the review process

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

Authors' conclusions

Implications for practice

There were no eligible randomised trials to be included in the review. There is no scientific evidence to support or refute the need for a booster dose of HB vaccine in healthy individuals with normal immune status who had fully responded to a complete course of vaccine.

Implications for research

We need randomised clinical trials to formulate future booster policies. 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. Evidence was not sufficient for adults older than 24 years vaccinated against hepatitis B. Hence, the need for a booster dose in these groups has to be investigated in randomised clinical trials as well. These trials ought to be conducted and reported according to the CONSORT-statement (www.consort-statement.org).

Acknowledgements

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 Reviewers: Tahany Awad, Denmark; Joseph Luis Mathew, India; Kristian Thorlund, Denmark.
Contact Editor: Christian Gluud, Denmark.

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 (AIR) 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 HBV infection?YesNo
Were they free of predisposing factors for immunodeficiency?YesNo
Were they screened for serologic markers of HBV 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 AIR to booster dose of hepatitis B vaccine versus placebo investigated?YesNo

Appendix 2. Search strategies

DatabasesTime of searchesSearch terms
The Cochrane Hepato-Biliary Group Controlled Trials RegisterMay 2010.vaccin* AND 'hepatitis B' AND boost*
The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryIssue 4, 2010.#1 MeSH descriptor 'Hepatitis B' explode all trees
#2 MeSH descriptor 'Vaccines' explode all trees
#3 MeSH descriptor 'Vaccination' explode all trees
#4 MeSH descriptor 'Immunization' explode all trees
#5 (#2 OR #3 OR #4)
#6 (#1 AND #5)
MEDLINE (Ovid SP)1950 to May 2010.#1 MeSH descriptor 'Hepatitis B' explode all trees
#2 MeSH descriptor 'Vaccines' explode all trees
#3 MeSH descriptor 'Vaccination' explode all trees
#4 MeSH descriptor 'Immunization' explode all trees
#5 (#2 OR #3 OR #4)
#6 (#1 AND #5)
#7 #6 NOT animal
#8 random* OR blind* OR placebo* OR meta-analys*
#9 #7 AND #8
EMBASE (Ovid SP)1980 to May 2010.#1 MeSH descriptor 'Hepatitis B' explode all trees
#2 MeSH descriptor 'Vaccines' explode all trees
#3 MeSH descriptor 'Vaccination' explode all trees
#4 MeSH descriptor 'Immunization' explode all trees
#5 (#2 OR #3 OR #4)
#6 (#1 AND #5)
#7 #6 NOT animal
#8 random* OR blind* OR placebo* OR meta-analys*
#9 #7 AND #8
Science Citation Index Expanded (http://apps.isiknowledge.com)1945 to May 2010.#1 TS=vaccin*
#2 TS='hepatitis B'
#3 #1 AND #2
#4 TS=(boost* OR follow-up OR add* OR supplem*)
#5 #3 AND #4
#6 TS=(random* OR blind* OR placebo* OR mask* OR meta-analys*)
#7 #5 AND #6

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  
Others  
SystemicFever  
Headache  
Malaise  
Irritability  
Rash  
Nausea  
Myalgia  
Arthralgia  
Others  

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

DomainJudgement
Sequence allocation generationLow risk of biasUncertain risk of biasHigh risk of bias
  • Low risk of bias. Sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice are adequate if performed by an independent adjudicator.

  • Uncertain risk of bias. The trial is described as randomised, but the method of sequence generation was not specified.

  • High risk of bias. The sequence generation method is not, or may not be, random. Quasi-randomised studies, those using dates, names, or admittance numbers in order to allocate patients are inadequate studies for our review and will be excluded for the assessment of benefits but not for harms.

Allocation concealmentLow risk of biasUncertain risk of biasHigh risk of bias
  • Low risk of bias. Allocation was controlled by a central and independent randomisation unit, opaque, sealed, and serially numbered envelopes or similar, so that intervention allocations could not have been foreseen in advance of, or, during enrolment.

  • Uncertain risk of bias. The trial was described as randomised, but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during enrolment.

  • High risk of bias, if the allocation sequence was known to the investigators who assigned participants, or if the study was quasi-randomised. Quasi-randomised studies will be excluded for the assessment of benefits but not for harms.

Blinding of participants, personnel, and outcome assessorsLow risk of biasUncertain risk of biasHigh risk of bias
  • Low risk of bias. Blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding.

  • Uncertain risk of bias. There is insufficient information to assess whether the type of blinding used is likely to induce bias on the estimate of effect.

  • High risk of bias. There is no blinding or incomplete blinding, and the outcome or the outcome measurement is likely to be influenced by lack of blinding.

Incomplete outcome dataLow risk of biasUncertain risk of biasHigh risk of bias
  • Low risk of bias. The underlying reasons for missingness are unlikely to make treatment effects departure from plausible values, or proper methods have been employed to handle missing data.

  • Uncertain risk of bias. There is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data is likely to induce bias on the estimate of effect.

  • High risk of bias. The crude estimate of effects (eg, complete case estimate) will clearly be biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory.

Selective outcome reportingLow risk of biasUncertain risk of biasHigh risk of bias
  • Low risk of bias. The trial protocol is available and all of the trial's pre-specified outcomes that are of interest in the review have been reported or similar.

  • Uncertain risk of bias. There is insufficient information to assess whether the magnitude and direction of the observed effect is related to selective outcome reporting.

  • High risk of bias. Not all of the trial's pre-specified primary outcomes have been reported or similar.

Baseline imbalanceLow risk of biasUncertain risk of biasHigh risk of bias
  • Low risk of bias. Tere was no baseline imbalance in important characteristics.

  • Uncertain risk of bias. The baseline characteristics were not reported.

  • High risk of bias. There was a baseline imbalance due to chance, or due to imbalanced exclusion after randomisation.

Other bias risksLow risk of biasUncertain risk of biasHigh risk of bias
  • Low risk of bias. The trial appears to be free of other components that could put it at risk of bias.

  • Uncertain risk of bias. The trial may or may not be free of other components that could put it at risk of bias.

  • High risk of bias. There are other factors in the trial that could put it at risk of bias, eg, for-profit involvement, authors have conducted trials on the same topic etc.

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

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.

Akbar Fotouhi (AF): assisted with reviewing and editing the protocol, and was responsible for the assessment of risk of bias in included studies, interpretation of results, and writing of the review.

Reza Majdzadeh (RM): assisted with reviewing and editing the protocol, and was responsible for interpretation of results and writing of the review.

Mahmood Mahmoodi (MM): assisted with reviewing and editing the protocol, and was responsible for the data analysis, interpretation of results, and writing of the review.

Aliakbar Haghdoost (AH): was responsible for the analysis, interpretation of results, and writing of the review.

Siavosh Nasseri-Moghaddam (SN): assisted with reviewing and editing the protocol, and was responsible for the reference searching, interpretation of results, and writing of the review.

Leila Ghalichi (LG): was responsible for article retrieval, study inclusion and exclusion, assessment of risk of bias in included studies, interpretation of results, and writing of the review.

Declarations of interest

We declare that we have no conflict of interest.

Sources of support

Internal sources

  • TUMS, Tehran, Iran.

    Department of Epidemiology and Biostatistics, School of Public Health, Tehran Univesity of Medical Science (TUMS)

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Ayerbe 2001A non-randomised clinical trial in which anamnestic response to a booster dose of hepatitis B vaccine was explored in a group of protected and non-protected vaccinees.
Belloni 2000A non-randomised clinical trial which explored anamnestic immune response to a booster dose in a single intervention group five years post primary vaccination without considering a control group.
Boxall 2004A non-randomised clinical trial investigating anamnestic immune response to a booster dose of vaccine in those individuals who were born to hepatitis B virus carrier mothers, who had received vaccine plus immunoglobulin during infancy.
Bryan 1997A non-randomised clinical trial exploring anamnestic immune response to a booster dose in two different intervention groups during the period less than five years post primary vaccination.
Bucher 1994A non-randomised clinical trial with two parallel intervention groups to investigate anamnestic immune response to two different regiments of booster doses five years after the initial immunisation, without considering a control group.
Chadha 2000A non-randomised clinical trial which was conducted to explore anamnestic immune response to a booster dose in two groups with different vaccination history ten years after the primary immunisation without considering a control group.
Chan 1991A randomised clinical trial which was conducted to explore anamnestic immune response to a booster dose during the first five years post primary vaccination in which two different booster doses were administered without considering any control group.
Coursaget 1986A non-randomised clinical trial in which individuals received booster doses one year after initial vaccination and were followed for the next six years in order to assess incidence of hepatitis B infection in comparison with non vaccinated individuals.
Da Villa 1996A non-randomised clinical trial which investigated anamnestic immune response to a booster dose in two groups of vaccinees after five and ten years from the last vaccination, without considering a control group.
Dahifar 2007A non-randomised clinical trial which was conducted to investigate anamnestic immune response to a booster dose in children, one or two years post primary immunisation.
Dahifar 2008A non-randomised clinical trial which explored anamnestic immune response to booster dose in a single intervention group five years post primary vaccination without considering a control group.
Davidson 1986A non-randomised clinical trial which assessed anamnestic immune response to booster dose in a single intervention group six to seven years after initial vaccination, without considering a control group.
Dentico 2002A non-randomised clinical trial with four parallel intervention groups enrolled in order to investigate anamnestic immune response to four different booster doses after the initial immunisation without considering a control group.
Durlach 2003A non-randomised clinical trial which was conducted to explore anamnestic immune response to a booster dose in a single intervention group 10 years post primary vaccination, without considering a control group.
Duval 2005A non-randomised clinical trial which investigated anamnestic immune response to two different regiments of booster doses in two parallel intervention groups five years after the initial immunisation, without considering a control group.
Floreani 2004A non-randomised clinical trial which was conducted to explore anamnestic immune response to a booster dose in a single intervention group six years after the initial vaccination, without considering a control group.
Gabbuti 2007A non-randomised clinical trial which explored anamnestic immune response to a booster dose in a single intervention group 11 years post primary vaccination, without considering a control group.
Gilca 2008A non-randomised clinical trial which was conducted to investigate anamnestic immune response to a booster dose in two groups of vaccinees after five and ten years from the last vaccination, without considering a control group.
Hammitt 2007A non-randomised clinical trial which was conducted to explore anamnestic immune response to a booster dose in a single intervention group 15 years after the primary immunisation, without considering a control group.
Laplanche 1987A randomised clinical trial, in which individuals received booster doses shortly (less than five years) after initial vaccination and were followed for the next five years to assess incidence of hepatitis B infection.
Li 1996A non-randomised clinical trial which investigated anamnestic immune response to a booster dose in a single intervention group seven years post primary vaccination, without considering a control group.
Li 1998A non-randomised clinical trial which explored anamnestic immune response to booster dose in a single intervention group six and half years after the initial immunisation, without considering a control group.
Lu 2004A non-randomised clinical trial which was conducted to explore anamnestic immune response to a booster dose in a single intervention group 15 years after the primary immunisation, without considering a control group.
Lu 2008aA non-randomised clinical trial which was conducted to investigate anamnestic immune response to a booster dose in a single intervention group 13 years after the primary immunisation, without considering a control group.
Lu 2008bA non-randomised clinical trial which was conducted to investigate anamnestic immune response to a booster dose in a single intervention group 15 years after the primary immunisation, without considering a control group.
Milne 1992aA non-randomised clinical trial which explored anamnestic immune response to a booster dose in a single intervention group five years after the initial vaccination, without considering a control group.
Milne 1992bA non-randomised clinical trial which assessed anamnestic immune response to a booster dose in a single intervention group five and half years post primary vaccination, without considering a control group.
Milne 1994A non-randomised clinical trial which investigated anamnestic immune response to booster dose in a single intervention group nine years after the initial immunisation, without considering a control group.
Peces 2001A non-randomised clinical trial which was conducted to explore anamnestic immune response to a booster dose in a single intervention group six years post primary vaccination, without considering a control group.
Petersen 2004A non-randomised clinical trial which enrolled seven parallel intervention groups to investigate anamnestic immune response to different doses and different types of a booster of hepatitis B vaccine during 5, 7, 8, 9, 10, and 12.5 years after the initial immunisation, without considering a control group.
Saffar 2004A non-randomised clinical trial which enrolled three parallel intervention groups to explore anamnestic immune response to three different booster doses 10 years post primary vaccination, without considering a control group.
Samandari 2007A non-randomised clinical trial which enrolled three parallel intervention groups to investigate anamnestic immune response to booster doses 6, 12, and 14 years after primary vaccination without considering a control group.
Saygun 2002A non-randomised clinical trial which was conducted to explore T cell proliferation in response to HBsAg stimulation in vaccinees, considering non immunised and uninfected individuals as control group.
Seto 2002A non-randomised clinical trial which was conducted to investigate anamnestic immune response to booster dose in a single intervention group six years post primary vaccination, without considering a control group.
Shih 1999A non-randomised community-based clinical trial which was conducted to evaluate long-term universal hepatitis B vaccination program during infancy and the effects of a booster dose on non-protected school age children, some of whom were born to hepatitis B virus carrier mothers.
Su 2007A non-randomised clinical trial which explored anamnestic immune response to a booster dose in a single intervention group 20 years post primary vaccination, without considering a control group.
Trivello 1992A non-randomised clinical trial which was conducted to explore anamnestic immune response to a booster dose in a single intervention group five years post primary vaccination, without considering a control group.
Trivello 1995A non-randomised clinical trial which was conducted to investigate anamnestic immune response to a booster dose in two parallel intervention groups with different vaccination history six years post primary vaccination, without considering a control group.
van der Sande 2007A randomised clinical trial which explored anamnestic immune response to a booster dose in both protected and non-protected vaccinees 15 years post primary vaccination, without simultaneously assessing the immune response in the control group.
Wang 2007A non-randomised clinical trial which was conducted to explore anamnestic immune response to a booster dose in a single intervention group 16 years after the initial immunisation, without considering a control group.
Watson 2001A non-randomised clinical trial which was conducted to assess anamnestic immune response to two different booster doses in two parallel intervention groups 13 years post primary vaccination, without considering a control group.
Williams 2001A randomised clinical trial which was conducted to investigate anamnestic immune response to two different booster doses in two parallel intervention groups nine years post primary vaccination, without considering a control group.
Williams 2003A non-randomised clinical trial which was conducted to explore anamnestic immune response to booster doses in two groups of vaccinees five and nine years after the primary vaccination, without considering a control group.
Wismans 1989A non-randomised clinical trial exploring anamnestic immune response to booster before five years from the initial vaccination.
Xueliang 2000A non-randomised clinical trial which was conducted to assess anamnestic immune response to a booster dose in a single intervention group 11 years after the initial immunisation, without considering a control group.
Zanetti 2005A randomised clinical trial which was conducted to explore anamnestic immune response to two different booster doses in two parallel intervention groups 10 years post primary vaccination, without considering a control group.
Zhang 1993A non-randomised clinical trial whose participants were children, born to hepatitis B virus carrier mothers.
Zhuang 1998A randomised placebo-controlled clinical trial with school age children to assess anamnestic immune response to a booster dose only three years after the primary vaccination.

Characteristics of studies awaiting assessment [ordered by study ID]

Aspinall 1995

MethodsDesign: unknown.
Follow-up: unknown.
ParticipantsUnknown.
InterventionsBooster dose of hepatitis B vaccine.
OutcomesAnamnestic immune response to a booster dose.
NotesNeither full text nor abstract was accessible.

Patel 2004

MethodsDesign: randomised clinical trial.
Follow-up: 10 years.
ParticipantsHealthy participants.
InterventionsBooster dose of hepatitis B vaccine versus nothing.
OutcomesAnamnestic immune response to a booster dose.
NotesA poster presentation, but full text was not accessible.

Petersen 1995

MethodsDesign: unknown.
Follow-up: 9 years.
ParticipantsHealthy participants.
InterventionsBooster dose of hepatitis B vaccine.
OutcomesAnamnestic immune response to a booster dose.
NotesNeither full text nor abstract was accessible.

Watson 1998

MethodsDesign: unknown.
Follow-up: unknown.
ParticipantsHealthy participants.
InterventionsBooster dose of hepatitis B vaccine.
OutcomesAnamnestic immune response to a booster dose.
NotesNeither full text nor abstract was accessible.

Yang 1995

MethodsDesign: unknown.
Follow-up: 7 years.
ParticipantsHealthy participants.
InterventionsBooster dose of hepatitis B vaccine.
OutcomesAnamnestic immune response to a booster dose.
NotesNeither full text nor abstract was accessible.

Ancillary