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. 2009 Sep 23;2009:0916.

Hepatitis B (prevention)

Suzanne Norris 1,#, Abdul Mohsen 2,#
PMCID: PMC2907831  PMID: 21726479

Abstract

Introduction

Nearly a third of the world’s population has been infected by hepatitis B at some point, and at least 350 million people have become chronic carriers. Progressive liver damage occurs in up to 25% of carriers. In areas of high endemicity, transmission occurs largely in childhood; from an infected mother to her baby, or between members of a household.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of vaccination against hepatitis B infection in countries with high endemicity? What are the effects of vaccination against hepatitis B infection in countries with low endemicity? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations, such as the US Food and Drug Administration (FDA), and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 51 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: selective vaccination of high-risk individuals; selective vaccination of people with chronic liver disease not caused by hepatitis B; universal vaccination of adolescents; and universal vaccination of infants.

Key Points

Nearly a third of the world's population has been infected by hepatitis B at some point, and at least 350 million people have become chronic carriers. Progressive liver damage occurs in up to 25% of carriers.

  • In areas of high endemicity, transmission occurs largely in childhood, from an infected mother to her baby, or between members of a household.

  • In areas of low endemicity, transmission usually occurs as a result of sexual activity, intravenous drug use, or occupational exposure.

  • The risk of developing hepatitis B depends largely on the vaccination policy of the country of residence, and routine vaccination of all infants is recommended by the WHO.

Selective vaccination of infants with recombinant or plasma-derived vaccines in countries with high endemicity of hepatitis B reduces occurrence and chronic carrier state.

  • Combining vaccine with hepatitis B immunoglobulin is more effective than vaccine alone.

Universal vaccination of infants with recombinant or plasma-derived vaccines, in countries with high endemicity of hepatitis B, reduces the risk of acute hepatitis, chronic carrier state, and complications of chronic infection, and may be more effective than selective vaccination of high-risk individuals.

Universal vaccination of infants or adolescents in low-endemic areas may reduce the risk of infection, or of developing a chronic carrier state, but we don't know how different vaccination strategies compare, as no studies have been done.

Selective vaccination of high-risk individuals in countries with low hepatitis B endemicity may prevent acute infection and development of a chronic carrier state.

  • Uptake of vaccination may be low, even in high-risk groups.

Vaccination is associated generally with mild adverse effects, although more serious autoimmune adverse effects can occur rarely.

We don't know whether selective vaccination of people with known chronic liver disease not caused by hepatitis B reduces subsequent infection rates, as few studies have been done.

The evidence reported here is the best available evidence for this type of intervention, and further research is unlikely to change the conclusions reached.

About this condition

Definition

Hepatitis B is a viral infectious disease with an incubation period of 40 to 160 days. Acute hepatitis B infection is characterised by anorexia, vague abdominal discomfort, nausea and vomiting, jaundice, and occasional fever. Illness is associated with deranged liver function tests (especially raised alanine transaminases) and the presence of serological markers of acute hepatitis B infection (e.g., hepatitis B surface antigen [HBsAg], or antibody to hepatitis B core antigen [anti-HBc IgM]).

Incidence/ Prevalence

The incidence of acute hepatitis B, and prevalence of its chronic carrier state, varies widely across the globe. In areas with high endemicity (HBsAg prevalence 8% or more; e.g., Southeast Asia and Africa), more than half of the population becomes infected at some point. In countries with low endemicity (HBsAg prevalence less than 2%; e.g., North America, Western Europe, and Australia), most of the population does not become infected. Nearly a third of the world's population has been infected by hepatitis B at some point, and at least 350 million people (5%–6% of the world's population) are currently chronic carriers of hepatitis B infection.

Aetiology/ Risk factors

In countries with high endemicity, most transmissions occur during childhood from an infected mother to her baby (vertical transmission) or from one family member to another (horizontal transmission). Horizontal transmission is thought to be an important route of hepatitis B infection during early childhood, and probably occurs mainly through unnoticed contact with blood from infected family members. In countries with high endemicity, the proportion of chronic HBsAg carriage attributable to vertical transmission has been estimated at 5% to 50%. The proportion of chronic HBsAg carriage attributable to horizontal transmission is not known, although one survey in China found that 27.2% of families had one or more HBsAg-positive members. In countries with low endemicity, most hepatitis B infections occur later — from sexual activity, intravenous drug use, or occupational exposure. Less frequent causes of infection include household contact, regular haemodialysis, transmission from a healthcare professional, and receipt of infected organs or blood products. The vaccination policy of a country is a large determinant of the risk of developing hepatitis B. Since the development of plasma-derived hepatitis B vaccine in the early 1980s, subsequently replaced by recombinant vaccine, many countries have adopted a policy of universal vaccination of infants. On the basis of disease burden, the WHO recommended that the hepatitis B vaccine be incorporated into routine infant and childhood vaccination programmes in countries with high endemicity by 1995 and in all countries by 1997. However, in many countries with low endemicity, universal vaccination policy remains controversial and has still not been adopted. Some of these countries have adopted a policy of selective vaccination of high-risk individuals. Others have adopted a universal adolescent vaccination policy.

Prognosis

Hepatitis B infection resolves after the acute infection in 90% to 95% of cases. In the remainder, it may result in several serious sequelae. Massive hepatic necrosis occurs in 1% of people with acute viral hepatitis, leading to a serious, and often fatal, condition called acute fulminant hepatitis. Between 2% and 10% of those infected as adults become chronic carriers, indicated by HBsAg persistence for more than 6 months. Chronic carriage is more frequent in those infected as children, and reaches up to 90% in those infected during the perinatal period. Between 20% and 25% of chronic carriers develop a progressive chronic liver disease. In about one quarter to one third of cases, this progresses to cirrhosis and hepatocellular carcinoma. These complications usually arise in older adults, and are major causes of mortality in populations with high hepatitis B endemicity. Observational studies suggest that, in these countries, almost 80% of chronic liver disease and cirrhosis are attributed to hepatitis B, and these complications lead to at least 1 million deaths every year worldwide.

Aims of intervention

To reduce the risk of acquiring hepatitis B infection in susceptible people, while minimising adverse effects of interventions.

Outcomes

Incidence of acute hepatitis B; Development of chronic carrier state; chronic liver disease, cirrhosis, and hepatocellular carcinoma secondary to hepatitis B; mortality secondary to hepatitis B infection and its chronic sequelae; and adverse effects of treatment.

Methods

Clinical Evidence search and appraisal June 2008. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2008, Embase 1980 to June 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, 2008, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the Review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We included all studies described as "open", "open label", or not blinded. We also searched for cohort, case-control, cross-sectional, and surveillance studies and included those with prospectively identified large populations (>1000). In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Hepatitis B (prevention).

Important outcomes Development of chronic carrier state, Incidence of hepatitis B, Mortality
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of vaccination against hepatitis B infection in countries with high endemicity?
6 RCTs (618 infants) Incidence of hepatitis B Selective vaccination of high-risk individuals versus placebo or no treatment 4 0 0 0 0 High
10 RCTs (at least 618 infants) Incidence of hepatitis B Vaccination plus immunoglobulin versus vaccination alone 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (127) Incidence of hepatitis B Universal vaccination of infants versus placebo or no vaccination 4 –2 0 0 0 Low Quality points deducted for sparse data and loss to follow-up
4 (>2013 children) Development of chronic carrier state Universal vaccination of infants versus placebo or no vaccination 4 –2 0 0 0 Low Quality points deducted for loss to follow-up and inclusion of observational studies
3 (>45 million children) Mortality Universal vaccination of infants versus placebo or no vaccination 2 –1 0 0 0 Very low Quality point deducted for loss to follow-up
1 (about 120,000 people) Incidence of hepatitis B Universal vaccination of infants versus selective vaccination in high-risk individuals 4 –2 0 0 0 Low Quality points deducted for problems with cluster methodology and incomplete reporting of results
1 (about 120,000 people) Development of chronic carrier state Universal vaccination of infants versus selective vaccination in high-risk individuals 4 –2 0 0 0 Low Quality points deducted for problems with cluster methodology and incomplete reporting of results
What are the effects of vaccination against hepatitis B infection in countries with low endemicity?
15 (7297) Incidence of hepatitis B Selective vaccination of high-risk individuals versus placebo or no vaccination 4 0 –1 0 0 Moderate Consistency point deducted for conflicting results
2 (at least 1926) Development of chronic carrier state Selective vaccination of high-risk individuals versus placebo or no vaccination 4 –3 0 0 0 Very low Quality points deducted for loss to follow-up, inclusion of non-RCT evidence, and incomplete reporting of results
1 (539) Mortality Selective vaccination of high-risk individuals versus placebo or no vaccination 4 –1 0 0 0 Moderate Quality point deducted for loss to follow-up
1 (at least 1000) Incidence of hepatitis B Universal vaccination of adolescents versus placebo or no vaccination 2 –1 0 0 0 Very low Quality point deducted for incomplete reporting of results
1 (2469) Incidence of hepatitis B Universal vaccination of infants versus placebo or no vaccination 2 –1 0 0 0 Very low Quality point deducted for incomplete reporting of results
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Chronic carrier state

A person is considered a chronic carrier if the HBsAg has been persistently positive for more than 6 months.

Countries with high hepatitis B endemicity

HBsAg prevalence 8% or higher.

Countries with low hepatitis B endemicity

HBsAg prevalence less than 2%.

Hepatitis B surface antigen (HBsAg)

A serological marker on the surface of hepatitis B virus. It indicates acute or chronic hepatitis B infection.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

High-risk vaccination strategy

In this strategy, hepatitis B vaccine is recommended in individuals and groups who are at high risk of hepatitis B because of their lifestyle, occupation, and other factors. These include close contact of a case or a carrier, babies born to infected mothers, parenteral drug misusers, individuals who change sexual partners frequently, homosexual or bisexual men, people with haemophilia, people on haemodialysis, healthcare workers, and residents of institutions for individuals with severe learning disabilities.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Protective efficacy

((R1 – R2)/R1) x 100, where R1 is the incidence of the event in the control population and R2 is the incidence of the event in the immunised population. This is the same as the relative risk reduction.

Recombinant vaccine

Contains HBsAg absorbed on aluminium hydroxide adjuvant and is prepared from yeast cells using recombinant DNA technology.

Universal vaccination strategy

In this strategy, routine hepatitis B vaccination is carried out for either all infants or adolescents through a national programme.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Dr Suzanne Norris, St James Hospital, Dublin, Ireland.

Dr Abdul Mohsen, Chelsea and Westminster Hospital, London, UK.

References

  • 1.Department of Health. Immunisation against infectious disease. London: HMSO, 1996. [Google Scholar]
  • 2.Kane M. Global programme for control of hepatitis B infection. Vaccine 1995;13(suppl 1):47–49. [DOI] [PubMed] [Google Scholar]
  • 3.Margolis HS. Hepatitis B virus infection. Bull World Health Organ 1998;76(suppl 2):152–153. [PMC free article] [PubMed] [Google Scholar]
  • 4.Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis 2002;2:395–403. [DOI] [PubMed] [Google Scholar]
  • 5.Kammerlander R, Zimmermann H. Transmission of hepatitis B. Soz Praventivmed 1998;43:S31–S33, S105–S107. [In French/German] [DOI] [PubMed] [Google Scholar]
  • 6.van Hattum J, Boland GJ, Jansen KG, et al. Transmission profile of hepatitis B virus infection in the Batam region, Indonesia. Evidence for a predominantly horizontal transmission profile. Adv Exp Med Biol 2003;531:177–183. [DOI] [PubMed] [Google Scholar]
  • 7.Yao GB. Importance of perinatal versus horizontal transmission of hepatitis B virus infection in China. Gut 1996;38:S39–S42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Yao JL. Perinatal transmission of hepatitis B virus infection and vaccination in China. Gut 1996;38:S37–S38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733–1745. [DOI] [PubMed] [Google Scholar]
  • 10.World Health Organization. Hepatitis B vaccine. Wkly Epidemiol Rec 1991;11. [Google Scholar]
  • 11.Edmunds WJ. Universal or selective immunisation against hepatitis B virus in the United Kingdom? A review of recent cost-effectiveness studies. Commun Dis Public Health 1998;1:221–228. [PubMed] [Google Scholar]
  • 12.Maddrey WC. Hepatitis B: an important public health issue. J Med Virol 2000;61:362–366. [DOI] [PubMed] [Google Scholar]
  • 13.Lee C, Gong Y, Brok J, et al. Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis. BMJ 2006;332:328–336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Xu ZY, Duan SC, Margolis HS, et al. Long-term efficacy of active postexposure immunization of infants for prevention of hepatitis B virus infection. United States-People's Republic of China Study Group on Hepatitis B. J Infect Dis 1995;171:54–60. [DOI] [PubMed] [Google Scholar]
  • 15.Fortuin M, Chotard J, Jack AD, et al. Efficacy of hepatitis B vaccine in the Gambian expanded programme on immunisation. Lancet 1993;341:1129–1131. [DOI] [PubMed] [Google Scholar]
  • 16.Viviani S, Jack A, Hall AJ, et al. Hepatitis B vaccination in infancy in the Gambia: protection against carriage at 9 years of age. Vaccine 1999;17:2946–2950. [DOI] [PubMed] [Google Scholar]
  • 17.Liao SS, Li RC, Li H, et al. Long-term efficacy of plasma-derived hepatitis B vaccine: a 15-year follow-up study among Chinese children. Vaccine 1999;17:2661–2666. [DOI] [PubMed] [Google Scholar]
  • 18.Liao SS, Li RC, Li H, et al. Long-term efficacy of plasma-derived hepatitis B vaccine among Chinese children: a 12-year follow-up study. World J Gastroenterol 1999;5:165–166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Perrin J, Coursaget P, Ntareme F, et al. Hepatitis B immunization of newborns according to a two dose protocol. Vaccine 1986;4:241–244. [DOI] [PubMed] [Google Scholar]
  • 20.Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 1997;336:1855–1859. [DOI] [PubMed] [Google Scholar]
  • 21.Lee CL, Ko YC. Hepatitis B vaccination and hepatocellular carcinoma in Taiwan. Pediatrics 1997;99:351–353. [DOI] [PubMed] [Google Scholar]
  • 22.Ni YH, Chang MH, Huang LM, et al. Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Intern Med 2001;135:796–800. [DOI] [PubMed] [Google Scholar]
  • 23.Khao JH, Hsy HM, Shau WY, et al. Universal hepatitis B vaccination and the decreased mortality from fulminant hepatitis in infants in Taiwan. J Pediatr 2001;139:349–352. [DOI] [PubMed] [Google Scholar]
  • 24.Da Villa G, Picciottoc L, Elia S, et al. Hepatitis B vaccination: universal vaccination of newborn babies and children at 12 years of age versus high risk groups. A comparison in the field. Vaccine 1995;13:1240–1243. [DOI] [PubMed] [Google Scholar]
  • 25.Da Villa G, Piccinino F, Scolastico C, et al. Long-term epidemiological survey of hepatitis B virus infection in a hyperendemic area (Afragola, southern Italy): results of a pilot vaccination project. Res Virol 1998;149:263–270. [DOI] [PubMed] [Google Scholar]
  • 26.Da Villa G, Romano L, Sepe A, et al. Impact of hepatitis B vaccination in a highly endemic area of south Italy and long-term duration of anti-HBs antibody in two cohorts of vaccinated individuals. Vaccine 2007;25:3133–3136. [DOI] [PubMed] [Google Scholar]
  • 27.Su FH, Chen JD, Cheng SH, et al. Waning-off effect of serum hepatitis B surface antibody amongst Taiwanese university students: 18 years post-implementation of Taiwan's national hepatitis B vaccination programme. J Viral Hepatitis 2008;15:14–19. [DOI] [PubMed] [Google Scholar]
  • 28.Arkachaisri T. Serum sickness and hepatitis B vaccine including review of the literature. J Med Assoc Thai 2002;85(suppl 2):S607–S612. [PubMed] [Google Scholar]
  • 29.Hanslik T, Vaillant JN, Audrain L, et al. Systemic lupus erythematosus and risk of hepatitis B vaccination: from level of evidence to prescription. Rev Med Interne 2000;21:785–790. [In French] [DOI] [PubMed] [Google Scholar]
  • 30.Bassily S, Kotkat A, Gray G, et al. Comparative study of the immunogenicity and safety of two dosing schedules of hepatitis B vaccine in neonates. Am J Trop Med Hygiene 1995;53:419–422. [DOI] [PubMed] [Google Scholar]
  • 31.Su FH, Chen JD, Cheng SH, et al. Seroprevalence of Hepatitis-B infection amongst Taiwanese university students 18 years following the commencement of a national Hepatitis-B vaccination program. J Medical Virol 2007;79:138–143. [DOI] [PubMed] [Google Scholar]
  • 32.Ni YH, Huang LM, Chang MH, et al. Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies. Gastroenterology 2007;132:1287–1293. [DOI] [PubMed] [Google Scholar]
  • 33.Chen W, Gluud C. Vaccines for preventing hepatitis B in health-care workers (Cochrane review). In: The Cochrane Library, Issue 4, 2005. Chichester, UK: John Wiley & Sons, LTd. SEarch date 2003. [DOI] [PubMed] [Google Scholar]
  • 34.Schroth RJ, Hitchon CA, Uhanova J, et al. Hepatitis B vaccination for patients with chronic renal failure. In: The Cochrane Library: Issue 4, 2005. Chichester, UK: John Wiley & Sons, Ltd. Search date 2003; primary sources: The Cochrane Hepato-Biliary Group Controlled Trials Register; The Cochrane Renal Group Controlled Trials Register; The Cochrane Trials Register; Pubmed/Medline; Embase; Current Clinical Practice Guidelines (Canadian Immunization Guide and Vaccine Preventable Diseases Surveillance Manual); Science Citation Index; and journals, published abstracts, and reference lists of articles. 15266500 [Google Scholar]
  • 35.Coutinho RA, Lelie N, Albrecht VL. Efficacy of a heat inactivated hepatitis B vaccine in male homosexuals: outcome of a placebo controlled double blind trial. BMJ 1983;286:1305–1308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Szmuness W, Stevens CE, Zang EA, et al. A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report. Hepatology 1981;1:377–385. [DOI] [PubMed] [Google Scholar]
  • 37.Francis DP, Hadler SC, Thompson SE, et al. The prevention of hepatitis B with vaccine. Report of the centers for disease control multi-center efficacy trial among homosexual men. Ann Intern Med 1982;97:362–366. [DOI] [PubMed] [Google Scholar]
  • 38.Roumeliotou-Karayannis A, Papaevangelou G, Tassopoulos N, et al. Post-exposure active immunoprophylaxis of spouses of acute viral hepatitis B patients. Vaccine 1985;3:31–34. [DOI] [PubMed] [Google Scholar]
  • 39.Geier DA, Geier MR. A case-control study of serious autoimmune adverse events following hepatitis B immunization. Autoimmunity 2005;38:295–301. [DOI] [PubMed] [Google Scholar]
  • 40.Chen W. Gluud C. Vaccines for preventing hepatitis B in health-care workers. In: The Cochrane Library, Issue 2, 2008. Chichester, UK: John Wiley & Sons, Ltd. Search date 2003. 10796693 [Google Scholar]
  • 41.Noto H, Terao T, Ryou S, et al. Combined passive and active immunoprophylaxis for preventing perinatal transmission of the hepatitis B virus carrier state in Shizuoka, Japan during 1980–1994. J Gastroenterol Hepatol 2003;18:943–949. [DOI] [PubMed] [Google Scholar]
  • 42.Yu O, Bohlke K, Hanson CA, et al. Hepatitis B vaccine and risk of autoimmune thyroid disease: a Vaccine Safety Datalink study. Pharmacoepidem Dr S 2007;16:736–745. [DOI] [PubMed] [Google Scholar]
  • 43.MacKellar DA, Valleroy LA, Secura GM, et al. Two decades after vaccine license: hepatitis B immunization and infection among young men who have sex with men. Am J Public Health 2001;91:965–971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Patrick DM, Bigham M, Ng H, et al. Elimination of acute hepatitis B among adolescents after one decade of an immunization program targeting Grade 6 students. Pediatr Infect Dis J 2003;22:874–877. [DOI] [PubMed] [Google Scholar]
  • 45.Dobson S, Scheifele D, Bell A. Assessment of a universal, school-based hepatitis B vaccination program. JAMA 1995;274:1209–1213. [PubMed] [Google Scholar]
  • 46.Dawar M, Patrick DM, Bigham M, et al. Impact of universal preadolescent vaccination against hepatitis B on antenatal seroprevalence of hepatitis B markers in British Columbia women. CMAJ 2003;168:703–704. [PMC free article] [PubMed] [Google Scholar]
  • 47.Bell A. Universal hepatitis B immunization: the British Columbia experience. Vaccine 1995;13:S77–S81. [DOI] [PubMed] [Google Scholar]
  • 48.Perz JF, Elm JL Jr, Fiore AE, et al. Near elimination of hepatitis B virus infections among Hawaii elementary school children after universal infant hepatitis B vaccination. Pediatrics 2006;118:1403–1408. [DOI] [PubMed] [Google Scholar]
  • 49.Fisher MA, Eklund SA, James SA, et al. Adverse events associated with hepatitis B vaccine in U.S. children less than six years of age, 1993 and 1994. Ann Epidemiol 2001;11:13–21. [DOI] [PubMed] [Google Scholar]
  • 50.Lewis E, Shinefield HR, Woodruff BA, et al. Safety of neonatal hepatitis B vaccine administration. Pediatr Infect Dis J 2001;20:1049–1054. [DOI] [PubMed] [Google Scholar]
  • 51.Niu MT, Davis DM, Ellenberg S. Recombinant hepatitis B vaccination of neonates and infants: emerging safety data from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J 1996;15:771–776. [DOI] [PubMed] [Google Scholar]
  • 52.Zanetti AR. Update on hepatitis B vaccination in Italy 10 years after its implementation. Vaccine 2001;19:2380–2383. [DOI] [PubMed] [Google Scholar]
  • 53.Harpaz R, McMahon BJ, Margolis HS, et al. Elimination of new chronic hepatitis B virus infections: results of the Alaska immunization program. J Infect Dis 2000;181:413–418. [DOI] [PubMed] [Google Scholar]
  • 54.Mallol-Mesnard N, Menegaux F, Auvrignon A, et al. Vaccination and the risk of childhood acute leukaemia: the ESCALE study (SFCE). Int J Epidemiol 2007;36:110–116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Rosman AS, Basu P, Galvin K, et al. Efficacy of a high and accelerated dose of hepatitis B vaccine in alcoholic patients: a randomised clinical trial. Am J Med 1997;103:217–222. [DOI] [PubMed] [Google Scholar]
  • 56.Arslan M, Wiesner RH, Sievers C, et al. Double-dose accelerated hepatitis B vaccine in patients with end-stage liver disease. Liver Transplant 2001;7:314–320. [DOI] [PubMed] [Google Scholar]
  • 57.Chin JE (ed). Control of communicable diseases. Washington: American Public Health Association, 2000. [Google Scholar]
  • 58.Andreoli TE, Carpenter CCJ, Griggs RC, et al (eds). Cecil essentials of medicine. Philadelphia: WB Saunders, 1993. [Google Scholar]
  • 59.Halliday ML, Kang LY, Rankin JG, et al. An efficacy trial of a mammalian cell-derived recombinant DNA hepatitis B vaccine in infants born to mothers positive for HBsAg, in Shanghai, China. Int J Epidemiol 1992;21:564–573. [DOI] [PubMed] [Google Scholar]
BMJ Clin Evid. 2009 Sep 23;2009:0916.

Selective vaccination of high-risk individuals (high-endemic areas)

Summary

Selective vaccination of infants with recombinant or plasma-derived vaccines, in countries with high endemicity of hepatitis B, reduces incidence of hepatitis B and development of chronic carrier state.

Combining vaccine with hepatitis B immunoglobulin is more effective than vaccine alone.

Benefits and harms

Selective vaccination of high-risk individuals versus placebo or no treatment:

We found one systematic review (search date 2004, 6 RCTs, 618 infants born to mother positive for HBsAg) comparing the protective efficacy of vaccination (using either recombinant vaccine or plasma-derived vaccine) or the protective efficacy of hepatitis B immunoglobulin versus placebo or no treatment.

Incidence of hepatitis B

Selective vaccination of high-risk individuals compared with placebo Vaccination (recombinant or plasma-derived), and hepatitis B immunoglobulin are more effective at decreasing the risk of hepatitis B occurrence in infants born to HBsAg-positive mothers in high-endemic areas (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Incidence of hepatitis B

Systematic review		 406 infants
4 RCTs in this analysis		 Risk of hepatitis B
with hepatitis B vaccination (recombinant or plasma-derived vaccine)
with placebo or no treatment
Absolute results not reported
RR 0.28
95% CI 0.20 to 0.40 		Moderate effect size hepatitis B vaccination

Systematic review		 212 infants
Data from 1 RCT		 Risk of hepatitis B
66/139 (47%) with hepatitis B immunoglobulin
68/73 (93%) with placebo or no intervention
RR 0.50
95% CI 0.41 to 0.60 		Small effect size hepatitis B immunoglobulin
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Development of chronic carrier state

No data from the following reference on this outcome.

Mortality

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 Number of infants unclear Adverse effects
with hepatitis B vaccine (recombinant or plasma-derived) or immunoglobulin
with placebo or no treatment
Absolute results not reported
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Vaccination plus immunoglobulin versus vaccination alone:

We found one systematic review (search date 2004, 10 RCTs, at least 618 infants born to mothers positive for HBsAg) comparing vaccination plus immunoglobulin versus vaccination alone.

Incidence of hepatitis B

Vaccination plus immunoglobulin compared with vaccination alone The risk of hepatitis B infection is further reduced by adding immunoglobulin to hepatitis B vaccine (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Incidence of hepatitis B

Systematic review		 Number of infants not reported
10 RCTs in this analysis		 Risk of hepatitis B
with hepatitis B vaccination plus immunoglobulin
with vaccination alone
Absolute results not reported
RR 0.54
95% CI 0.41 to 0.73 		Moderate effect size hepatitis B vaccination plus immunoglobulin
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Development of chronic carrier state

No data from the following reference on this outcome.

Mortality

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Selective vaccination of high-risk individuals versus universal vaccination of infants:

See option on universal vaccination of infants.

Further information on studies

Analyses of plasma-derived vaccine and recombinant vaccine individually showed that both vaccines significantly decreased the risk of hepatitis B occurrence, and found no significant difference between plasma-derived and recombinant vaccine on hepatitis B occurrence (4 RCTs; 382 infants; RR 1.00, 95% CI 0.70 to 1.42).

One RCT identified by the review comparing plasma-derived vaccine versus recombinant vaccine reported minor adverse reactions (5%; mainly irritability and rash) after vaccination of infants born to HBsAg-positive mothers.

The review found no significant difference in hepatitis B occurrence between high-dose and low-dose vaccine (plasma-derived vaccine: 3 RCTs; RR 0.97, 95% CI 0.55 to 1.68; recombinant vaccine: 1 RCT; RR 0.78, 95% CI 0.31 to 1.94). Three-dose plasma-derived vaccine plus hepatitis B immunoglobulin did not significantly prevent hepatitis B occurrence compared with two-dose plasma-derived vaccine plus hepatitis B immunoglobulin (1 RCT; RR 0.50, 95% CI 0.05 to 5.28). Plasma-derived vaccine given for the first time at birth did not significantly differ from plasma-derived vaccine given for the first time at 1 month of age with regard to the number of newborn infants having hepatitis B occurrence (1 RCT; RR 0.70, 95% CI 0.18 to 2.77). Multiple hepatitis B immunoglobulin plus plasma-derived vaccine compared with single hepatitis B immunoglobulin plus plasma-derived vaccine did not significantly reduce the risk of hepatitis B occurrence (2 RCTs; RR 0.87, 95% CI 0.30 to 2.47).

Comment

Selective vaccination of high-risk individuals versus universal vaccination of infants:

See comment on universal vaccination of infants.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Sep 23;2009:0916.

Universal vaccination of infants (high-endemic areas)

Summary

Universal vaccination of infants with recombinant or plasma-derived vaccines, in countries with high endemicity of hepatitis B, reduces the risk of acute hepatitis, chronic carrier state, and complications of chronic infection, and may be more effective than selective vaccination of high-risk individuals.

Vaccination of children born to hepatitis B surface antigen (HBsAg)-positive mothers prevents development of a chronic carrier state compared with placebo.

Benefits and harms

Universal vaccination of infants versus placebo or no vaccination:

We found four RCTs reported in five publications and observational data collected before, and after, mass vaccination programmes in Taiwan and Italy comparing hepatitis B vaccine versus placebo or no vaccine. We found two other non-systematic reviews assessing connective tissue disorders and recombinant vaccine. One of the reviews provided only narrative data on incidence of systemic lupus erethymatosus (see further information on studies). This review also identified one RCT conducted in Egypt that assessed only local reactions after vaccine.

Incidence of hepatitis B

Universal vaccination compared with placebo or no vaccination Universal vaccination of infants using plasma-derived vaccines may be more effective at protecting children from acute hepatitis B events (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Incidence of hepatitis B

RCT		 480 infants Acute hepatitis B events 1 year
0/68 (0%) with plasma-derived vaccine
5/59 (9%) with placebo
Protective efficacy 100%
95% CI not reported
P = 0.046 		Effect size not calculated hepatitis B vaccine
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No data from the following reference on this outcome.

Development of chronic carrier state

Universal vaccination compared with placebo or no vaccination Universal vaccination of infants may be more effective at reducing the risk of becoming a chronic carrier of hepatitis B at age 4 and 15 years (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Development of chronic carrier state

RCT		 1864 infants Protective efficacy (proportion of children who were HBsAg positive) 4 years
4/720 (0.6%) with adding hepatitis B vaccine to Expanded Program Immunization
103/816 (13%) with Expanded Program Immunization alone
Protective efficacy 94%
95% CI 84% to 98%
This trial has a 31% loss to follow-up, although sensitivity analysis found that vaccination reduced the chronic carrier state even after taking this into account 		Effect size not calculated hepatitis B vaccine

RCT		 1864 infants Protective efficacy (proportion of children who were HBsAg positive) 9 years
4/677 (0.5%) with adding hepatitis B vaccine to Expanded Program Immunization
99/823 (12%) with Expanded Program Immunization alone
Protective efficacy 90%
95% CI 79% to 95%
This trial has a 31% loss to follow-up, although sensitivity analysis found that vaccination reduced the chronic carrier state even after taking this into account 		Effect size not calculated hepatitis B vaccine

RCT		 649 children, aged 3-36 months, with no serological markers for previous infection Protective efficacy (proportion of children who were HBsAg positive) 5 years
0/152 (0%) with universal hepatitis B vaccination
24/190 (13%) with placebo
Protective efficacy 100%
95% CI not reported
P <0.001
Loss to follow-up was particularly high in this study (83%) but, owing to a paucity of data, it has been included 		Effect size not calculated hepatitis B vaccine

RCT		 649 children, aged 3-36 months, with no serological markers for previous infection Protective efficacy (proportion of children who were HBsAg positive) 12 years
3/171 (2%) with universal hepatitis B vaccination
18/179 (10%) with placebo
Protective efficacy 82%
95% CI not reported
P <0.01
Loss to follow-up was particularly high in this study (83%) but, owing to a paucity of data, it has been included 		Effect size not calculated hepatitis B vaccine

RCT		 649 children, aged 3-36 months, with no serological markers for previous infection Protective efficacy (proportion of children who were HBsAg positive) 15 years
1/52 (2%) with universal hepatitis B vaccination
9/54 (17%) with placebo
Protective efficacy 88%
95% CI not reported
P <0.001
Loss to follow-up was particularly high in this study (83%) but, owing to a paucity of data, it has been included 		Effect size not calculated hepatitis B vaccine

RCT		 513 children, aged 3–36 months, with no serological markers for previous infection
Subgroup analysis		 Protective efficacy (proportion of children who were HBsAg positive) 12 years
1/167 (0.6%) with universal hepatitis B vaccination
14/183 (8%) with placebo
Protective efficacy 92%
95% CI not reported
P <0.0001 		Effect size not calculated hepatitis B vaccine

RCT		 480 infants Carrier rates 1 year
0/68 (0%) with plasma derived hepatitis B vaccination
4/59 (97%) with placebo
Protective efficacy 100%
Reported as significant
P value not reported 		Effect size not calculated hepatitis B vaccine

Cohort study		 1915 children, younger than 15 years, and 559 people, aged 15 to 20, in Taipei City Carrier rates 15 years post mass vaccination
9/1357 (0.7%) with vaccination (children under 15 years)
39/559 (7%) with no vaccination (people aged 15 to 20 years)
P <0.001 		Effect size not calculated mass vaccination

Cohort study		 5875 students Carrier rates 19 yeaqrs post mass vaccination
13/670 (2%) with vaccination (students born in 1976)
11/76 (14%) with no vaccination (students born in 1987)
P <0.0001 across all cohort years 		Effect size not calculated mass vaccination

Cohort study		 1961 students Chronic carrier state 15 years after vaccination programme
11/1090 (1%) with vaccination (students born in 1978)
72/871 (8%) with no vaccination (students born in 1997)
P <0.001
This study had possible misclassification bias because the final diagnoses of hepatitis events were made only clinically by general practitioners and were not validated 		Effect size not calculated vaccination programme

Cohort study		 4230 students Proportion of people positive for HBsg 18 years after universal hepatitis B vaccination
14/1540 (1%) with vaccination (in 2006)
361/2690 (13%) with no vaccination (in 1976)
P <0.001 		Effect size not calculated universal hepatitis B vaccination
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No data from the following reference on this outcome.

Mortality

Universal vaccination compared with placebo or no vaccination Universal vaccination with a plasma-derived vaccine may be more effective at reducing mortality secondary to hepatocellular carcinoma and mortality of fulminant hepatitis (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality

Cohort study		 Total number of infants in analysis unclear (45 million infants born in time-frames assessed) Mortality as a result of hepatocellular carcinoma
0.33 per 1 million children with universal vaccination (after July 1990)
0.72 per 1 million children with no universal vaccination (before July 1990)
P <0.01 comparision of 1990 cohort v other 2 cohorts combined 		Effect size not calculated hepatitis B vaccine

Cohort study		 Children aged 1–9 years; total number in analysis unclear (7 million in cohorts assessed) Mortality as a result of hepatocellular carcinoma
with universal vaccination programme (1993)
with no universal vaccination programme (1983)
Standardised mortality ratio 1993 = 0.34
95% CI 0.14 to 0.89
Standardised mortality ratio 1983 = 1.25
95% CI 0.70 to 2.25
Comparative statistical results not reported

Cohort study		 Children younger than 15 years (total number in analysis unclear) Mortality from fulimiant hepatitis
1.71 (range 0.3–4.6) per 100,000 infants with universal vaccination (between 1985 and 1998)
5.36 (range 2.9–6.7) per 100,000 infants with no universal vaccination (between 1975 and 1984)
Significance not reported
These results should be interpreted with caution as the study also found a lower overall average mortality ratio during the period from 1985 to 1998 than during the period from 1975 to 1984 (0.32, 95% CI 0.24 to 0.42)

Cohort study		 Children younger than 15 years (number in analysis unclear) Average mortality ratio
with universal vaccination (1986 to 1998)
with no universal vaccination (1975 to 1984)
Mortality ratio 0.32
95% CI 0.24 to 0.42 		vaccination
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No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Non-systematic review		 166,757 children in New Zealand Adverse effects
with plasma-derived vaccine
with baseline
Absolute results not reported

Non-systematic review		 43,618 people in Alaska Adverse effects
with plasma-derived vaccine
with baseline
Absolute results not reported

RCT
3-armed trial 		590 infants in Egypt
In review 		Local reactions
5/178 (3%) with hepatitis B vaccine (recombinant) plus routine vaccination at birth
12/167 (7%) with hepatitis B vaccine (recombinant) plus routine vaccination at 2
3/191 (2%) with routine vaccination only
P <0.05 for hepatitis B vaccine (recombinant) plus routine vaccination at 2 months v routine vaccination only 		Effect size not calculated routine vaccination only

RCT
3-armed trial 		590 infants in Egypt
In review 		Fever
10/178 (6%) with hepatitis B vaccine (recombinant) plus routine vaccination at birth
12/167 (7%) with hepatitis B vaccine (recombinant) plus routine vaccination at 2
4/191 (2%) with routine vaccination only
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.

Universal vaccination of infants versus selective vaccination in high-risk individuals:

We found one cluster RCT in Italy (two towns with a population of about 60,000 each) comparing a universal vaccination strategy (all infants and adolescents) versus vaccination of high-risk groups only.

Incidence of hepatitis B

Universal vaccination compared with selective vaccination We don't know how a universal vaccination strategy (using either plasma-derived vaccines or recombinant vaccines) and selective vaccination of high-risk individuals compare at reducing the incidence of hepatitis B (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Incidence of hepatitis B

RCT		 2 towns with an approximate population of 60,000 people each (multi-centre cluster-randomised trial) Mean incidence of hepatitis B
3/100,000 between 1991 and 1993 with universal vaccination of all infants and adolescents in town 1
63/100,000 between 1963 and 1990 with no universal vaccination in town 1
15/100,000 between 1991 and 1993 with selective vaccination of high-risk adults in town 2
55/100,000 between 1963 and 1990 with no selective vaccination in town 2
No direct comparison between groups
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Development of chronic carrier state

Universal vaccination compared with selective vaccination of high-risk individuals We don't know how a universal vaccination strategy (using either plasma-derived vaccines or recombinant vaccines) and selective vaccination of high-risk individuals compares at reducing the incidence of hepatitis B (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Incidence of hepatitis B

RCT		 2 towns with an approximate population of 60,000 people each (multi-centre cluster-randomised trial) Prevalence of HBsAg positivity
change from 13% at baseline in 1978 in all adults and adolescents to 3% in 1993 with universal vaccination of all infants and adolescents
change from 14% at baseline in 1978 in high-risk individuals to 7% in 1993 with selective vaccination of high-risk adults
Absolute results not reported
Significance not assessed
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Adverse effects

No data from the following reference on this outcome.

Further information on studies

The average annual incidence of hepatocellular carcinoma was significantly reduced in children born after the introduction of universal vaccination in 1984 (mortality per 1000 children: 0.70 in the 1981–1986 cohort, 0.57 in the 1987–1990 cohort, and 0.36 in the 1991–1994 cohort; P <0.01 for comparison between before and after the 1990 cohorts).

The lower mortality as a result of hepatocellular carcinoma in children after the introduction of mass vaccination contrasted with no change in the adult standardised mortality ratio secondary to hepatocellular carcinoma during this period (standardised mortality ratio 1.14, 95% CI 1.07 to 1.20 in 1983 v 1.28, 95% CI 1.21 to 1.35 in 1993; comparative statistical results not reported).

Several of the studies mentioned in the benefits section had high loss to follow-up. However, owing to a paucity of data in this field, the studies were included despite the possible limitations.

The cluster RCT conducted in the two towns in southern Italy was possibly exposed to cross-contamination and the effects of migration. Despite these possible limitations, the difference between the declines in the incidences of hepatitis was overwhelmingly supportive of a universal vaccination strategy.

The second non-systematic review (search date 2000; number of studies not reported) found no evidence (from case series and case reports) of a causal link between systematic lupus erythematosus and recombinant vaccine.

The RCT used strict inclusion criteria excluding underweight children and those with other disorders.The trial claimed to have lost only 10% of participants at follow-up, with no losses caused by adverse effects, but it did not state how this was assessed.

Comment

Universal vaccination of infants versus placebo or no treatment:

One study carried out 18 years after the implementation of universal vaccination in Taiwan found the prevalence of hepatitis B immunity had declined through a waning-off effect of serum hepatitis B surface antibodies (anti-HBs), which may prove that a booster dose of vaccination at this age or earlier should be considered to maintain efficacy. However, another study was carried out 20 years after implementation of universal vaccination (measured serum HBsAg at ages 3 to 4 years and 18 to 19 years) and reported no increase in the proportion of HBsAg-seropositive people in the birth cohort born after vaccination implementation (proportion of HBsAg seropositivity in 1985–1986 birth cohort: 2.2% in 1989 v 2.1% in 2004; absolute numbers not reported; significance not reported).

Clinical guide

The RCTs and observational studies reported represent the best available evidence for universal vaccination of infants in countries of high endemicity. The intervention has been categorised as beneficial, and further research is unlikely to change this conclusion.

Substantive changes

Universal vaccination of infants Two observational studies added, which found that universal vaccination of infants reduced the proportion of hepatitis B carriers compared with no vaccination. Categorised as Beneficial.

BMJ Clin Evid. 2009 Sep 23;2009:0916.

Selective vaccination of high-risk individuals (low-endemic areas)

Summary

Selective vaccination of high-risk individuals in countries with low hepatitis B endemicity may prevent acute infection and development of a chronic carrier state.

Uptake of vaccination may be low, even in high-risk groups.

We found no clinically important results from RCTs about the effects of selective vaccination in high-risk individuals compared with universal vaccination in countries with low endemicity.

Benefits and harms

Selective vaccination of high-risk individuals versus placebo or no vaccination:

We found two systematic reviews (search date 2003; search date 2003) and five RCTs.

Incidence of hepatitis B

Selective vaccination of high-risk individuals compared with placebo or no vaccine In countries with low endemicity, plasma-derived hepatitis B vaccination seems more effective at reducing the incidence of acute hepatitis B (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Incidence of hepatitis B

Systematic review		 2697 healthcare workers
4 RCTs in this analysis		 Hepatitis B events mean follow up 14.5 months
38/1365 (3%) with plasma-derived hepatitis B vaccination
71/1332 (5%) with placebo
RR 0.51
95% CI 0.35 to 0.73 		Small effect size hepatitis B vaccine

Systematic review		 1850 people on haemodialysis
7 RCTs in this analysis		 Incidence of hepatitis B
52/933 (6%) with hepatitis B vaccination
83/917 (9%) with placebo
RR 0.50
95% CI 0.20 to 1.24 		Not significant

RCT		 800 homosexual men in the Netherlands
7 RCTs in this analysis		 Incidence of acute hepatitis infections 21.5 months
17/397 (4%) with plasma-derived hepatitis B vaccination
56/403 (14%) with placebo
RR 0.31
95% CI 0.18 to 0.52
NNT 11
95% CI 8 to 18 		Moderate effect size plasma-derived hepatitis B vaccination

RCT		 1083 homosexual men in the US
7 RCTs in this analysis		 Acute hepatitis B events
13/448 (3%) with plasma-derived hepatitis B vaccination
77/431 (21%) with placebo
P <0.0001 		Effect size not calculated hepatitis B vaccination

RCT		 1402 homosexual men in the US
7 RCTs in this analysis		 Hepatitis B events
58/482 (9%) with plasma-derived hepatitis B vaccination
110/443 (21%) with placebo
P <0.001 		Effect size not calculated hepatitis B vaccination

RCT		 160 heterosexual partners of infected people
7 RCTs in this analysis		 Acute hepatitis B events 9 months
12/75 (16%) with vaccination
13/71 (18%) with placebo
P >0.5
The RCT was able to recruit only 75% of the eligible partners, which might make the results unrepresentative 		Effect size not calculated hepatitis B vaccination
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No data from the following reference on this outcome.

Development of chronic carrier state

Selective vaccination of high-risk individuals compared with placebo or no vaccine Selective vaccination seems no more effective at reducing mortality in people on haemodialysis (very low quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Development of chronic carrier state

RCT		 1083 homosexual men in the US
7 RCTs in this analysis		 HBsAG positive
12/448 (3%) with plasma-derived hepatitis B vaccination
90/448 (24%) with placebo
protective efficacy 87%
P <0.0001 		Effect size not calculated hepatitis B vaccination
Mothers infected with hepatitis B in Japan
7 RCTs in this analysis		 Proportion of neonates born to HBsAg-positive mothers who did not develop carrier state
980/1030 (95%) with recombinant hepatitis B vaccination plus hepatitis B immunoglobulin (post 1986)
no data with no vaccination (pre-1986)		 Effect size not calculated
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No data from the following reference on this outcome.

Mortality

Selective vaccination of high-risk individuals compared with placebo or no vaccine Selective vaccination seems no more effective at reducing mortality in people on haemodialysis (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality

Systematic review		 1850 people on haemodialysis
7 RCTs in this analysis		 Mortality
113/273 (41%) with vaccination
117/266 (44%) with placebo
RR 1.39
95% CI 0.79 to 2.44 		Not significant
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No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 2697 healthcare workers
4 RCTs in this analysis		 Proportion of people who had adverse effects
with plasma-derived hepatitis B vaccination
with placebo
Absolute results not reported
OR 1.13
95% CI 0.95 to 1.35 		Not significant

Systematic review		 2697 healthcare workers
4 RCTs in this analysis		 Severity of systemic adverse effects
with plasma-derived hepatitis B vaccination
with placebo
Absolute results not reported
OR 1.60
95% CI 0.64 to 4.04 		Not significant

Systematic review		 2697 healthcare workers
4 RCTs in this analysis		 Severity of local adverse effects
with plasma-derived hepatitis B vaccination
with placebo
Absolute results not reported
OR 1.09
95% CI 0.90 to 1.33 		Not significant

Systematic review		 539 people
2 RCTs in this analysis		 Proportion of people who had adverse effects
27/273 (10%) with hepatitis B vaccination
19/266 (7%) with placebo
RR 1.39
95% CI 0.79 to 2.44 		Not significant

RCT		 800 homosexual men in the Netherlands
7 RCTs in this analysis		 Sore arm after first dose
64% with vaccination
45% with placebo
Absolute numbers not reported
P <0.001 		Effect size not calculated placebo

RCT		 1083 homosexual men in the US
7 RCTs in this analysis		 Incidence of adverse effects
24% with plasma-derived hepatitis B vaccination
21% with placebo
Absolute numbers not reported
Reported as not significant
P value not reported 		Not significant

RCT		 1402 homosexual men in the US
7 RCTs in this analysis		 Sore arm
9% with plasma-derived hepatitis B vaccination
6% with placebo
Absolute numbers not reported
P <0.001 		Effect size not calculated placebo

RCT		 1402 homosexual men in the US
7 RCTs in this analysis		 Dizziness
3% with plasma-derived hepatitis B vaccination
0.6% with placebo
P <0.001 		Effect size not calculated placebo
Open in a new tab

No data from the following reference on this outcome.

Selective vaccination of high-risk individuals versus universal vaccination:

We found no systematic review, RCTs, or observational studies.

Further information on studies

Both RCTs from the US with homosexual men had a high loss to follow-up (19% and 25%) during 2 years, raising the possibility of bias. However, these were included due to a paucity of data in this area.

Hepatitis B prevalence is about 1.4% in Japan, and occurs mainly because of vertical transmission from infected mother to neonate.

Comment

Risk of autoimmune disorders:

A retrospective case control study of serious autoimmune adverse effects reported in the US found that, compared with tetanus-containing vaccine, adults receiving the hepatitis B vaccine had significantly increased odds ratios for multiple sclerosis, optic neuritis, vasculitis, arthritis, alopecia, lupus erythematosus, rheumatoid arthritis, and thrombocytopenia (multiple sclerosis: OR 5.2, 95% CI 1.9 to 20, P <0.0003; optic neuritis: OR 14, 95% CI 2.3 to 560, P <0.0002; vasculitis: OR 2.6, 95% CI 1.03 to 8.7, P <0.04; arthritis: OR 2.01, 95% CI 1.3 to 3.1, P < 0.0003; alopecia: OR 7.2, 95% CI 3.2 to 20, P <0.0001; lupus erythematosus: OR 9.1, 95% CI 2.3 to 76, P <0.0001; rheumatoid arthritis: OR 18, 95% CI 3.1 to 740, P <0.0001; thrombocytopenia: OR 2.3, 95% CI 1.02 to 6.2, P <0.04). The study reported that minimal confounding or systematic error was observed. However, such reactions are rare and results should be interpreted with caution because of the retrospective nature of the study. One retrospective cohort study reported in the US investigated a postulated association between hepatitis B vaccination and thyroid disease. The study compared 355 Graves' disease cases and 418 Hashimoto's thyroiditis cases versus 1102 age-matched, gender-matched controls. It found that there was no significant difference between the thyroid disease and control groups in the rate of hepatitis B vaccination (Graves' disease: hepatitis B vaccinations in 15.1% of controls v 19.2% of Graves' disease cases, OR 0.90, 95% CI 0.62 to 1.32, absolute figures not reported; Hashimoto's thyroiditis: hepatitis B vaccinations in 15.1% of controls v 15.3% of Hashimoto's thyroiditis cases, OR 1.23, 95% CI 0.87 to 1.73, absolute figures not reported).

Clinical guide:

One cross-sectional study from the US suggests poor uptake, and a high prevalence of chronic carrier state in homosexual men, despite a national high-risk vaccination programme. This may be an underestimate of the actual problem because only 62% were approached out of all eligible men, and only 62% of these agreed to take part in the study.

Substantive changes

Selective vaccination of high-risk individuals No new evidence on effects of selective vaccination of high-risk individuals. One retrospective cohort study added to harms found no evidence of a link between autoimmune thyroid disease and hepatitis B vaccine. Categorised as Likely to be beneficial.

BMJ Clin Evid. 2009 Sep 23;2009:0916.

Universal vaccination of adolescents (low-endemic areas)

Summary

We found no clinically important results from RCTs about the effects of universal adolescent vaccination compared with no vaccination or other vaccination strategies in low-endemic areas.

Benefits and harms

Universal vaccination of adolescents versus placebo or no vaccination:

We found no systematic review or RCTs. We found one observational study evaluating the effects of a mass vaccination programme for all preadolescent students in British Columbia and Canada from 1992.

Incidence of hepatitis B

Universal vaccination compared with placebo or no vaccination Universal vaccination programmes may reduce the risk of acute hepatitis B in adolescents in low endemic populations (very low quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Incidence of hepatitis B

Cohort study		 Mass vaccination programme for all preadolescent students in British Columbia, Canada, from 1992; total number of people from the general population (all age groups) in this analysis not reported (at least 1,000) Incidence of acute hepatitis B in total population
2 people per 100,000 with mass vaccination programme in 2001
7 people per 100,000 with no mass vaccination in 1993
Significance not assessed
Reduction is suggestive of acute hepatitis B virus elimination in the immunised adolescent cohort

Cohort study		 Mass vaccination programme for all preadolescent students in British Columbia, Canada, from 1992; total number of people aged 12-21 in this analysis not reported
Subgroup analysis		 Incidence of acute hepatitis B in people aged 12-21 years
1.7 people per 100,000 with mass vaccination programme in 2001
0 people per 100,000 with no mass vaccination in 1993
Significance not assessed
Reduction is suggestive of acute hepatitis B virus elimination in the immunised adolescent cohort
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Development of chronic carrier state

No data from the following reference on this outcome.

Mortality

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Cohort study		 41,494 students aged 11 years Adverse effects
with vaccine
with no vaccine
Absolute results not reported
Open in a new tab

No data from the following reference on this outcome.

Universal vaccination of adolescents versus other vaccination strategies:

We found no systematic review, RCTs, or observational studies.

Further information on studies

Comment

We found one cross-sectional survey of hepatitis B infection markers in a random sample of 1215 pregnant women aged 15 to 44 years in British Columbia, Canada. From this cohort, researchers assessed the prevalence of HBsAg among 15- to 19-year-old girls, 7 years after the start of an adolescent vaccination programme (begun in 1992). It reported no cases of HBsAg positivity in that age group. However, the prevalence of HBsAg among women aged 15 to 44 years was 1.4% in the full cohort, consisting mainly of people not vaccinated under the programme. The survey does not provide causal evidence on the efficacy of the adolescent vaccination strategy, but it does suggest that the strategy may be protective against developing chronic carrier state. We found no strong evidence on the effects of the adolescent vaccination strategy adopted in many parts of the US and Canada. Evaluation of adolescent vaccination schemes in Canada did not include the primary outcome measures adopted in this review. Surveillance data from the US and Canada have indicated few serious adverse reactions. The results are based on self-reported events, and there was no control group.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Sep 23;2009:0916.

Universal vaccination of infants (low-endemic areas)

Summary

We found no clinically important results from RCTs about the effects of universal vaccination of infants compared with no vaccination or compared with other vaccination strategies in infants in low-endemic areas.

Observational evidence suggests that universal vaccination reduces rates of hepatitis B.

Benefits and harms

Universal vaccination of infants versus placebo or no vaccination:

We found no RCTs, but we found one observational study assessing the efficacy of universal vaccination in countries with low endemicity of hepatitis B. We also found four retrospective cohort studies that only assessed adverse effects.

Incidence of hepatitis B

Universal vaccination compared with placebo or no vaccination Universal vaccination may reduce the risk of hepatitis B in school children in low endemic areas (very low quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Incidence of hepatitis B

Cohort study		 2469 elementary school students aged 6 to 9 years Past or present hepatitis B virus infection
6/2469 (0.24%) with hepatitis B vaccination in 1997
with
Compared with a 1989 survey, these prevalences represented declines of:
97% in chronic hepatitis B virus infections
90% in resolved hepatitis B virus infections
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No data from the following reference on this outcome.

Development of chronic carrier state

No data from the following reference on this outcome.

Mortality

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Cohort study		 6515 children under 6 years of age Arthritis
with recombinant vaccine
with no vaccine
Absolute results not reported
OR 5.91
95% CI 1.05 to 33.14 		Large effect size no vaccine

Cohort study		 6515 children under 6 years of age Acute ear infection
with recombinant vaccine
with no vaccine
Absolute results not reported
OR 1.60
95% CI 1.00 to 2.58 		Not significant

Cohort study		 6515 children under 6 years of age Pharyngitis
with recombinant vaccine
with no vaccine
Absolute results not reported
OR 1.41
95% CI 0.95 to 2.09 		Not significant

Cohort study		 5655 children in the US Adverse effects reported to health services the first 21 days after birth
27/3302 (0.8%) with vaccination
26/2353 (1.1%) with no vaccination
P value not reported

Cohort study		 Post-marketing surveillance data of recombinant vaccine in the US between 1991and 1995 Adverse effects
with recombinant hepatitis B vaccine
with
Absolute results not reported
There were 18 neonatal deaths between 1991 and 1998 after hepatitis B vaccinations, but no causal link was established between these deaths and vaccination. There was no suggestion of a link between hepatitis B vaccination and neurological or other serious adverse reactions

Cohort study		 Surveillance data from Italy (1991–2000) Adverse effects
with recombinant vaccine
with
Absolute results not reported
There were 19 serious post-vaccination adverse effects, none of which was linked to multiple sclerosis or any other serious neurological disease
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No data from the following reference on this outcome.

Universal vaccination of infants versus other vaccination strategies:

We found no systematic review, RCTs, or observational studies.

Further information on studies

The incidence of symptomatic acute hepatitis B in Hawaiian children and adolescents aged 19 years or older decreased from 4.5 cases per 100,000 in 1990 to 0 between 2002 and 2004. To date, the last reported case in a child aged under 15 years in Hawaii occurred in 1996.

Comment

The Hawaiian study suggests that hepatitis B prevention goals are being met through routine vaccination and related prevention programmes among US children. A retrospective cohort study performed in Alaska (7 villages, 533 children aged 10 years or under) did not meet our inclusion criteria of 1000 participants minimum. It found a marked decline in the prevalence of chronic carrier state after the adoption of universal vaccination strategy (prevalence of HBsAg 3.1% between 1982 and 1987, and 0% between 1993 and 1994; statistical significance not reported). Two cohort studies, both with a large sample size, found conflicting results regarding adverse effects. However, none reported any serious adverse reactions. Neither study validated their data from other sources. The first cohort study had a potential for non-response bias because the people who participated may not be representative of the general population. The second cohort study analysed adverse effects reported only to hospitals and may therefore have underestimated the frequency of events.

Risk of childhood leukaemia:

One retrospective cohort study (776 cases, and 1681 age- and gender-matched controls) investigated the potential association of hepatitis B vaccination and childhood acute leukaemia in France. It found no significant difference in the rate of hepatitis B vaccination between children with acute leukaemia and control (250/696 [36%] in acute leukaemia case group v 510/1434 [36%] in the control group, OR 1.0, 95% CI 0.8 to 1.3).

Substantive changes

Universal vaccination of infants No new evidence on the effects of universal vaccination of infants added. One retrospective cohort study added to harms found no evidence of a link between acute leukaemia and hepatitis B vaccination. Categorised as Likely to be beneficial.

BMJ Clin Evid. 2009 Sep 23;2009:0916.

Selective vaccination of people with known chronic liver disease not caused by hepatitis B

Summary

We don't know whether selective vaccination of people with known chronic liver disease not caused by hepatitis B reduces subsequent infection rates, as no high-quality, large studies have been done.

Benefits and harms

Selective vaccination of people with known chronic liver disease not caused by hepatitis B:

We found no systematic review, RCTs, or large observational studies comparing the effects of vaccination versus no vaccination on rates of hepatitis B in people with chronic liver disease. We found one RCT that assessed only adverse effects.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 110 people with alcoholism Adverse effects
with standard dose (20 micrograms at 0, 1, 3, and 6 months)
with high dose (40 micrograms at 0, 1, 3, and 6 months)
Adverse effects included infrequent, transient local arm soreness during vaccination and fever, diarrhoea, or headache in 3/110 (3%) people
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Further information on studies

Comment

Clinical guide:

Observational data from cohort suggests that post-transplant hepatitis B vaccination reduces the prevalence of anti-HBsAg antibodies; for example, one obsevational study (353 people transplanted for liver diseases other than hepatitis B) found a prevalence of 36% before transplantation compared with 11.6% after transplantation.

Substantive changes

No new evidence

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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