Advertisement

Hepatitis B vaccination: The key towards elimination and eradication of hepatitis B

  • Ding-Shinn Chen
    Correspondence
    Tel.: +886 2 23562176; fax: +886 2 23317624.
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University College of Medicine and Hepatitis Research Center, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan
    Search for articles by this author
Open AccessPublished:February 03, 2009DOI:https://doi.org/10.1016/j.jhep.2009.01.002
      Hepatitis B virus infection is a global health problem. Worldwide, about 360 million people are chronically infected with the virus. They continue to spread the virus to others and are themselves at risk of chronic liver diseases and hepatocellular carcinoma. The infection can now be treated by antivirals or interferons and the transmission route can be interrupted. Nevertheless, the most effective means is to immunize all susceptible individuals, especially young children, with safe and efficacious vaccines. The combined efforts of vaccination, effective treatment and interruption of transmission make elimination of the infection plausible and may eventually lead to eradication of the virus. Because hepatitis B vaccination has a key role in the control of hepatitis B, properties of this vaccine, its effectiveness in pre-exposure and post-exposure settings, duration of protection after vaccination and the need of booster doses are discussed. Mass hepatitis B vaccination in children decreases the carriage of the virus, and the diseases associated with acute and chronic infection, including hepatocellular carcinoma. Challenges that need to be solved to expand mass vaccination, and the strategies towards elimination and eventual eradication of hepatitis B in the world are also discussed.

      Keywords

      1. Introduction

      Hepatitis B virus (HBV) infection is one of the most common and important human viral infections. The infection can cause acute and chronic liver diseases, ranging from fulminant hepatitis to cirrhosis and eventually hepatocellular carcinoma (HCC) [
      • Chen D.S.
      From hepatitis to hepatoma: lessons from type B viral hepatitis.
      ]. Worldwide, as many as 360 million people are chronically infected with HBV, and ∼1 million deaths are attributed to its infection [
      • Margolis H.S.
      Fact sheets for candidate diseases for elimination or eradication. Hepatitis B virus infection.
      ]. Hence, control of HBV infection is extremely important. Strategies to fight against the infection comprise interrupting the route of transmission, treating chronically infected patients as well as treating susceptible individuals with immunoproplylaxis [
      • Kao J.H.
      • Chen D.S.
      Global control of hepatitis B virus infection.
      ].
      As we enter the fifth decade of the fight against HBV following its discovery, advances in vaccine development/implementation and antiviral therapies have shed more light on the elimination and eradication of HBV infection [
      • Fenner F.
      Candidate viral diseases for elimination or eradication.
      ]. Although current antiviral treatments using pegylated interferons or nucleos(t)ide analogs are effective for chronic hepatitis B, chronic HBV carriage is not easy to eliminate, as shown by the frequent persistence of hepatitis B surface antigen (HBsAg) in those who have responded well to the available treatments [
      • Hoofnagle J.H.
      • Doo E.
      • Liang T.J.
      • Fleischer R.
      • Lok A.S.F.
      Management of hepatitis B: Summary of a clinical research workshop.
      ]. On the other hand, from the very beginning, the hepatitis B vaccine has proved to prevent HBV infection effectively [
      • Szmuness W.
      • Stevens C.E.
      • Harley E.J.
      • Zang E.A.
      • Oleszko W.R.
      • William D.C.
      • et al.
      Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States.
      ,
      • Maupas P.
      • Chiron P.
      • Barin F.
      • Coursaget P.
      • Goudeau A.
      • Perrin J.
      • et al.
      Efficacy of hepatitis B vaccine in prevention of early HBsAg carrier state in children. Controlled trial in an endemic area (Senegal).
      ]. Vaccination of infants against hepatitis B, especially those born to HBV carrier mothers [
      • Beasley R.P.
      • Hwang L.Y.
      • Lee G.C.Y.
      • Lan C.C.
      • Roan C.H.
      • Huang F.Y.
      • et al.
      Prevention of perinatally transmitted hepatitis B virus infection with hepatitis B immune globulin and hepatitis B vaccine.
      ] is the most effective way to control the spread of HBV. And thus, universal infant vaccination will be the key to the elimination and subsequent eradication of hepatitis B. Elimination and eradication of hepatitis B require long-term commitment all over the world to continue the vaccination as well as interrupting the routes of transmission, treating the chronic HBV carriers, so that the infection is completely stopped. Because of the important role of hepatitis B vaccine in the control of hepatitis B, the current status of hepatitis B vaccination is reviewed.

      2. The hepatitis B vaccine

      In 1982, two hepatitis B vaccines from France and the United States were licensed. They were subunit vaccines containing 22-nm HBsAg particles made from plasma of chronic HBsAg carriers. The preparations undergo vigorous inactivation steps and are highly purified, and aluminum hydroxide is added as an adjuvant. The vaccine is preserved with thimerosal.
      Millions of doses of the first-generation plasma-derived vaccines have been used, and the effectiveness and safety records are excellent. However, concerns on the safety of human blood products always exist, especially after the discovery of human immunodeficiency virus (HIV) in the early 80’s [
      • Barre-Sinoussi F.
      • Chermann J.C.
      • Rey F.
      • Nugeyre M.T.
      • Chamaret S.
      • Gruest J.
      • et al.
      Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS).
      ]. Meanwhile, recombinant DNA technology has matured to such an extent that it has led to the satisfactory production of HBsAg in the yeast, Saccharomyces cerevisiae. The yeast-derived HBsAg was then used for vaccination, also showing excellent effectiveness and safety. Nowadays, it has generally replaced plasma-derived vaccines. Recombinant DNA vaccines can also be produced by inserting plasmids containing HBsAg genes into mammalian cells.
      Although the current vaccines are highly effective with a rate of 94–98% in protecting from chronic HBV infection for at least 20 years [
      • Ni Y.H.
      • Huang L.M.
      • Chang M.H.
      • Yen C.J.
      • Lu C.Y.
      • You S.L.
      • et al.
      Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
      ], they are far from perfect. There are still some populations in which the non-response rate is substantial, such as the elderly, smokers, obese individuals, those with chronic hepatic or chronic renal diseases. This resulted in more immunogenic hepatitis B vaccines being developed by incorporating HBV DNA sequences coding for pre-S1 and pre-S2 protein into the vector used for recombinant DNA technology in manufacture [
      • Shapira M.Y.
      • Zeira E.
      • Adler R.
      • Shouval D.
      Rapid seroprotection against hepatitis B following the first dose of a pre-S1/pre-S2/S vaccine.
      ,
      • Young M.D.
      • Schneider D.L.
      • Zuckerman A.J.
      • Du W.
      • Dickson B.
      • Maddrey W.C.
      • et al.
      Adult hepatitis B vaccination using a novel triple antigen recombinant vaccine.
      ]. Additionally, improvement of the adjuvants to make the vaccine more immunogenic has also been tried [
      • Kundi M.
      New hepatitis B vaccine formulated with an improved adjuvant system.
      ].
      To decrease the number of injections that are needed in routine immunizations to infants, combination vaccines containing HBsAg have been produced. The components of these combination vaccines include diphtheria, tetanus toxoids and acellular pertussis or whole-cell pertussis; Hemophilus influenzae type b; inactivated poliovirus; and hepatitis A virus. Any combination vaccine should demonstrate adequate efficacy as compared with individual vaccines. Pentavalent [
      • Pichichero M.E.
      • Bernstein H.
      • Blatter M.M.
      • Schuerman L.
      • Cheuvart B.
      • Holmes S.J.
      • et al.
      Immunogenitity and safety of a combination diphtheria, tetanus toxoid, acellular pertussis, hepatitis B, and inactivated poliovirus vaccine coadministered with a 7-valent pneumococcal conjugate vaccine and a Haemophilus influenzae type b conjugate vaccine.
      ,
      • Ortega-Barria E.
      • Kanra G.
      • Leroux G.
      • Bravo L.
      • Safary A.
      • Lefevre I.
      • et al.
      The immunogenicity and reactogenicity of DTPw-HBV/Hib 2.5 combination vaccine: results from four phase III multicenter trials across five continents.
      ] and hexavalent [
      • Mallet E.
      • Belohradsky B.H.
      • Lagos R.
      • Gothefors L.
      • Camier P.
      • Carriere J.P.
      • et al.
      A liquid hexavalent combined vaccine against diphtheria, tetanus, pertussis, poliomyelitis, Hemophilus infuluenzae type B and hepatitis B: review of immunogenicity and safety.
      ] combination vaccines have been developed successfully recently. The combination vaccine not only decreases the number of injections but also increases the coverage rates of vaccination [
      • Marshall G.S.
      • Happe L.E.
      • Lunacsek O.E.
      • Szymanski M.D.
      • Woods C.R.
      • Zahn M.
      • et al.
      Use of combination vaccines is associated with improved coverage rates.
      ]. The development of hepatitis B vaccines and the public health strategy of hepatitis B vaccination have been reviewed recently [
      • Shouval D.
      Hepatitis B vaccines.
      ,
      • Hollinger F.B.
      • Bell B.
      • Levy-Bruhl D.
      • Shouval D.
      • Wiersma S.
      • Van Damme P.
      Hepatitis A and B vaccination and public health.
      ].
      The vaccine should be kept at 2–8 °C and should never be frozen. It is relatively heat-stable [
      • Van Damme P.
      • Cramm M.
      • Safary A.
      • Vandepapeliere P.
      • Meheus A.
      Heat stability of a recombinant DNA hepatitis B vaccine.
      ], the immunogenicity does not change when the vaccine is stored for up to one month at ambient temperature [
      • Hipgrave D.B.
      • Tran T.N.
      • Huong V.M.
      • Dat D.T.
      • Nga N.T.
      • Long H.T.
      • et al.
      Immunogenicity of a locally produced hepatitis B vaccine with the birth dose stored outside the cold chain in rural Vietnam.
      ] or even at tropical temperature [
      • Otto B.F.
      • Suarnawa I.M.
      • Stewart T.
      • Nelson C.
      • Ruff T.A.
      • Widjava A.
      At-birth immunization against hepatitis B using a novel pre-filled immunization device stored outside the cold chain.
      ]. The heat stability helps greatly to deliver the vaccine in places where refrigeration is not available.

      3. Effectiveness of vaccination

      Hepatitis B vaccination is highly effective in both pre-exposure and post-exposure prophylaxis. Antibody to HBsAg (anti-HBs) is neutralizing and serum levels of ≥10 mIU/mL are protective.

      3.1 Pre-exposure settings

      The most extensively studied populations for pre-exposure prophylaxis are homosexuals and health-care workers. Randomized, double blind, placebo-controlled clinical trials have demonstrated a protective efficacy of 80–88% in male homosexuals [
      • Szmuness W.
      • Stevens C.E.
      • Harley E.J.
      • Zang E.A.
      • Oleszko W.R.
      • William D.C.
      • et al.
      Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States.
      ,
      • Odaka N.
      • Eldred L.
      • Cohn S.
      • Munoz A.
      • Fields H.A..
      • Fox R.
      • et al.
      Comparative immunogenicity of plasma and recombinant hepatitis B vaccines in homosexual men.
      ,
      • Francis D.P.
      • Hadler S.C.
      • Thompson S.E.
      • Maynard J.E.
      • Ostrow D.G.
      • Attman N.
      • et al.
      The prevention of hepatitis B with vaccine: report of the centers for disease control multi-center efficacy trial among homosexual men.
      ,
      • Coutinho K.A.
      • Lelie N.
      • Albrecht-Van Lent P.
      • Reerink-Brongers E.E.
      • Stoutjesdijk L.
      • Dees P.
      • et al.
      Efficacy of a heat inactivated hepatitis B vaccine in male homosexuals: outcome of a placebo-controlled double blind trial.
      ]. In health-care workers, hepatitis B vaccine appears to be efficacious [
      • Jefferson T.
      • Demicheli V.
      • Deeks J.
      • MacMillan A.
      • Sassi F.
      • Pratt M.
      Vaccines for preventing hepatitis B in health-care workers.
      ], especially in high-risk health-care workers, such as staff of renal hemodialysis units [
      • Szmuness W.
      • Stevens C.E.
      • Harley E.J.
      • Zang E.A.
      • Alter H.J.
      • Taylor P.E.
      • et al.
      Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection.
      ,
      • Crosnier J.
      • Jungers P.
      • Courouce A.M.
      • Laplanche A.
      • Benhamou E.
      • Degos F.
      • et al.
      Randomised placebo-controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units: I. Medical staff.
      ,
      • Desmyter J.
      • Colaert J.
      • De Groote G.
      • Reynders M.
      • Reerink-Brongers E.E.
      • Lelie P.N.
      • et al.
      Efficacy of heat-inactivated hepatitis B vaccine in haemodialysis patients and staff: double-blind placebo-controlled trial.
      ]. Patients with end-stage renal disease (ESRD) on hemodialysis are also protected by the vaccine [
      • Desmyter J.
      • Colaert J.
      • De Groote G.
      • Reynders M.
      • Reerink-Brongers E.E.
      • Lelie P.N.
      • et al.
      Efficacy of heat-inactivated hepatitis B vaccine in haemodialysis patients and staff: double-blind placebo-controlled trial.
      ,
      • Crosnier J.
      • Jungers P.
      • Courouce A.M.
      • Laplanche A.
      • Benhamou E.
      • Degos F.
      • et al.
      Randomised placebo-controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units: II. Haemodialysis patients.
      ,
      • Centers for Disease Control and Prevention
      Recommendations for preventing transmission of infections among chronic dialysis patients.
      ], however, not all studies demonstrated that ESRD patients receiving hemodialysis benefit from hepatitis B vaccination [
      • Stevens C.E.
      • Alter H.J.
      • Taylor P.E.
      • Zang E.A.
      • Harley E.J.
      • Szmuness W.
      Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy.
      ,
      • Schroth R.J.
      • Hitchon C.A.
      • Uhanova J.
      • Noreddin A.
      • Taback S.P.
      • Moffatt M.E.
      • et al.
      Hepatitis B vaccination for patients with chronic renal failure.
      ]. Part of the reason may be the lower immune response to the vaccine in these patients. The poor response is attributed to malnutrition, uremia and the generalized immunosuppression state in this population. Patients with serum creatinine ≥4 mg/dL have been shown to respond less effectively after hepatitis B vaccination (86% vs. 37%) [
      • Fraser G.M.
      • Ochana N.
      • Fenyves D.
      • Neumann L.
      • Chazan R.
      • Niv Y.
      • et al.
      Increasing serum creatinine and age reduce the response to hepatitis B vaccine in renal failure patients.
      ]. Those with glomerular filtration rate <10 mL/min, >60 years of age, and diabetes mellitus are less likely to seroconvert after immunization [
      • DaRoza G.
      • Loewen A.
      • Djurdjev O.
      • Love J.
      • Kempston C.
      • Burnett S.
      • et al.
      Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: earlier is better.
      ]. Efficient hemodialysis improves the response to hepatitis B vaccine [
      • Kovacic V.
      • Sain M.
      • Vukman V.
      Efficient haemodialysis improves the response to hepatitis B virus vaccination.
      ,
      • Ibrakim S.
      • el-Din S.
      • Bazzal I.
      Antibody level after hepatitis B vaccination in hemodialysis patients: impact of dialysis adequacy, chronic inflammation, local endemicity and nutritional status.
      ]. A coexisting hepatitis C virus infection may reduce the effectiveness of the vaccine in patients on maintenance hemodialysis [
      • Navarro J.F.
      • Teruel J.L.
      • Mateos M.L.
      • Marcen R.
      • Ortuno J.
      Antibody level after hepatitis B vaccination in hemodialysis patients: influence of hepatitis C virus infection.
      ]. The poor response to hepatitis B vaccine can be rescued with reinforced vaccination protocols by increasing the dose or number of the vaccines [
      • Benhamou E.
      • Courouce A.M.
      • Jungers P.
      • Laplanche A.
      • Degos F.
      • Brangier J.
      • et al.
      Hepatitis B vaccine: randomized trial of immunogenicity in hemodialysis patients.
      ,
      • Beleed K.
      • Wright M.
      • Eadington D.
      • Farr M.
      • Sellars L.
      Vaccination against hepatitis B infection in patients with end-stage renal disease.
      ]. Changing the route of vaccine administration from intramuscular to intradermal injections has also been claimed to improve the immunogenicity and may be cost-effective [
      • Fabrizi F.
      • Andrulli S.
      • Bacchini G.
      • Corti M.
      • Locatelli F.
      Intradermal versus intramuscular hepatitis B re-vaccination in non-responsive chronic dialysis patients: a prospective randomized study with cost-effectiveness evaluation.
      ,
      • Micozkadioglu H.
      • Zumrutdal A.
      • Torun D.
      • Sezer S.
      • Ozdemir F.N.
      • Haberal M.
      Low-dose intradermal vaccination is superior to high-dose intramuscular vaccination for hepatitis B in unresponsive hemodialysis patients.
      ]. However, other studies did not reach the same conclusion. The results of intradermal or intramuscular injections are almost the same, although the dose of hepatitis B vaccine can be reduced [
      • Mettang T.
      • Schenk U.
      • Thomas S.
      • Machleidt C.
      • Klefer T.
      • Fischer F.P.
      • et al.
      Low-dose intradermal versus intramuscular hepatitis B vaccination in patients with end-stage renal failure. A preliminary study.
      ,
      • Charest A.F.
      • McDougall J.
      • Goldstein M.B.
      A randomized comparison of intradermal and intramuscular vaccination against hepatitis B virus in incident hemodialysis patients.
      ]. Because the dosage and number of intradermal injections differed in different studies, and how long the anti-HBs induced by the inoculation will last is unclear, a firm conclusion cannot be drawn.
      For subjects infected with HIV, the responses after hepatitis B vaccination are suboptimal, either to plasma-derived vaccines or recombinant vaccines [
      • Carne C.A.
      • Weller I.V.
      • Waite J.
      • Briggs M.
      • Pearce F.
      • Adler M.W.
      • et al.
      Impaired responsiveness of homosexual men with HIV antibodies to plasma-derived hepatitis B vaccines.
      ,
      • Collier A.C.
      • Corey L.
      • Murphy V.L.
      • Handsfield H.H.
      Antibody to human immunodeficiency virus (HIV) and suboptimal response to hepatitis B vaccination.
      ,
      • Zuin G.
      • Principi N.
      • Tornaghi R.
      • Paccagnini S.
      • Re M.
      • Massironi E.
      • et al.
      Impaired response to hepatitis B vaccine in HIV infected children.
      ,
      • Bruguera M.
      • Cremades M.
      • Salinas R.
      • Costa J.
      • Grau M.
      • Sans J.
      Impaired response to recombinant hepatitis B vaccine in HIV infected persons.
      ]. Based on a total of 447 subjects, relatively adequate CD4+ T-cells of ≥500/mm3 and lower HIV viral loads of ≤1000 copies/mL ensure immune responses to hepatitis B vaccine [
      • Laurence J.C.
      Hepatitis A and B immunizations of individuals infected with human immunodeficiency virus.
      ]. Nevertheless, those whose CD4+ T-cell counts and HIV viral loads are less favorable should not be denied the vaccination. A reinforced protocol as that used for those with other types of immune suppression can be employed and post-vaccination monitoring can also be conducted [
      • Laurence J.C.
      Hepatitis A and B immunizations of individuals infected with human immunodeficiency virus.
      ]. The response to hepatitis B vaccine in patients with acquired immune deficiency syndrome (AIDS) treated with highly active anti-retroviral therapy (HAART) may recuperate in adults [
      • Laurence J.C.
      Hepatitis A and B immunizations of individuals infected with human immunodeficiency virus.
      ,
      • Paitoonpong L.
      • Suankratay C.
      Immunological response to hepatitis B vaccination in patients with AIDS and virologic response to highly active antiretroviral therapy.
      ] and children [
      • Pippi F.
      • Bracciale L.
      • Stolzuoli L.
      • Giaccherini R.
      • Montomoli E.
      • Gentitle C.
      • et al.
      Serological response to hepatitis B virus vaccine in HIV-infected children in Tanzania.
      ].
      Patients with chronic liver disease also have suboptimal responses to hepatitis B vaccination. In addition to age and genetic predisposition, the severity of liver disease and the underlying etiology also play a critical role. For example, chronic alcoholics have inadequate responses to the hepatitis B vaccine, especially when the liver disease is overt [
      • Degos F.
      • Duhamel G.
      • Brechot C.
      • Nalpas B.
      • Courouce A.M.
      • Tron F.
      • et al.
      Hepatitis B vaccination in chronic alcoholics.
      ,
      • Mendenhall C.
      • Roselle G.A.
      • Lybecker L.A.
      • Marshall L.E.
      • Grossman C.J.
      • Myre S.A.
      • et al.
      Hepatitis B vaccination: response of alcoholic with and without liver injury.
      ]. In patients with non-hepatitis B chronic liver disease who receive liver transplant, the anti-HBs seroconversion rate is low after hepatitis B vaccination [
      • Carey W.
      • Pimentel R.
      • Westveer M.K.
      • Vogt D.
      • Broughan T.
      Failure of hepatitis B immunization in liver transplant recipients: results of a prospective trial.
      ,
      • Loinaz C.
      • de Juanes J.R.
      • Gonzales E.M.
      • Lopez A.
      • Lumbreras C.
      • Gomez R.
      • et al.
      Hepatitis B vaccination results in 140 liver transplant recipients.
      ,
      • Arslan M.
      • Wiesner R.H.
      • Sievers C.
      • Egan K.
      • Zein N.N.
      Double-dose accelerated hepatitis B vaccine in patients with end-stage liver disease.
      ]. The responses in those transplanted for HBV-related cirrhosis are especially poor, even after a reinforced triple course of vaccination [
      • Angelico M.
      • di Paolo D.
      • Trinito M.O.
      • Patrolati A.
      • Araco A.
      • Zazza S.
      • et al.
      Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis.
      ] or a double course of recombinant vaccine containing pre-S1, pre-S2 and S protein [
      • Karasu Z.
      • Ozacar T.
      • Akarca U.
      • Ersoz G.
      • Erensoy S.
      • Gunsar F.
      • et al.
      HBV vaccination in liver transplant recipients: not an effective strategy in the prophylaxis of HBV recurrence.
      ], only few patients have adequate levels of anti-HBs.
      Hepatitis B active immunization after liver transplant, if responsive in the transplant recipient, can prevent HBV recurrence following withdrawal of hepatitis B immune globulin (HBIG) [
      • Albeniz Arbizu E.
      • Barcena Marugan R.
      • Oton Nieto E.
      • Carrera Alonso E.
      • Garcia Gonzalez M.
      • Moreno Garica J.
      • et al.
      Prophylaxis of recurrent hepatitis B virus by vaccination after liver transplant: preliminary results.
      ]. Protection was especially evident in Taiwanese pediatric patients in a recent study [
      • Lin C.C.
      • Chen C.L.
      • Concejero A.
      • Wang C.C.
      • Wang S.H.
      • Liu Y.W.
      • et al.
      Active immunization to prevent de novo hepatitis B virus infection in pediatric live donor liver transplant.
      ]. In the study, all the 60 patients had received hepatitis B vaccination previously in a national infant hepatitis B vaccination program [
      • Chen D.S.
      • Hsu N.H.M.
      • Sung J.L.
      • Hsu T.C.
      • Hsu S.T.
      • Kuo Y.T.
      • et al.
      A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
      ]. The results imply that in the future, after universal infant vaccination against HBV is widely implemented, pre-transplant booster with HBV vaccines will very likely prevent the occurrence of post-transplant de novo or recurrent HBV infection.
      Responses to hepatitis B vaccine are also low in the recipients of renal transplant [
      • Feuerhake A.
      • Muller R.
      • Lauchart W.
      • Pichlmayr R.
      • Schmidt F.W.
      HBV vaccination in recipients of kidney allografts.
      ,
      • Jacobson I.M.
      • Jaffers G.
      • Dienstag J.L.
      • Tolkoff-Rubin N.E.
      • Cosimi A.B.
      • Delmonico F.
      • et al.
      Immunogenicity of hepatitis B vaccine in renal transplant recipients.
      ]. Increased dose and intradermal route of vaccination have also been tried to improve the immunogenicity with some success [
      • Choy B.Y.
      • Peiris J.S.
      • Chan T.M.
      • Lo S.K.
      • Lui S.L.
      • Lai K.N.
      Immunogenicity of intradermal hepatitis B vaccination in renal transplant recipients.
      ]. Because age of the patient has been shown to correlate with immune response to hepatitis B vaccine in patients with ESRD [
      • Fabrizi F.
      • Martin P.
      • Dixit V.
      • Bunnapradist S.
      • Dulai G.
      Meta-analysis: the effect of age on immunological response to hepatitis B vaccine in end-stage renal disease.
      ], and the immunogenicity is much higher if the vaccine is given before renal transplantation [
      • Lefebure A.F.
      • Verpooten G.A.
      • Couttenye M.M.
      • DeBroe M.E.
      Immunogenicity of a recombinant DNA hepatitis B vaccine in renal transplant patients.
      ], hepatitis B vaccination should be given as early as possible for patients with ESRD, preferably before renal transplantation.
      The poor response to hepatitis B vaccine can be improved by a different route of vaccine administration (see above), increased dose and frequency of vaccination [
      • Benhamou E.
      • Courouce A.M.
      • Jungers P.
      • Laplanche A.
      • Degos F.
      • Brangier J.
      • et al.
      Hepatitis B vaccine: randomized trial of immunogenicity in hemodialysis patients.
      ,
      • Beleed K.
      • Wright M.
      • Eadington D.
      • Farr M.
      • Sellars L.
      Vaccination against hepatitis B infection in patients with end-stage renal disease.
      ,
      • Horlander J.C.
      • Boyle N.
      • Manam R.
      • Schenk M.
      • Herring S.
      • Kwo P.Y.
      • et al.
      Vaccination against hepatitis B in patients with chronic liver disease awaiting liver transplantation.
      ,
      • Aziz A.
      • Aziz S.
      • Li D.S.
      • Murphy L.
      • Leone N.
      • Kennedy M.
      • et al.
      Efficacy of repeated high-dose hepatitis B vaccine (80 μg) in patients with chronic liver disease.
      ]. The adjuvant can also be improved. A new adjuvant system containing 3-deacylated monophosphoryl lipid A and a natural saponin molecule from Quillaja saponaria in an oil/water emulsion has been claimed to yield a better immune response of the vaccine, although the protective antibody declines rapidly [
      • Bienzle U.
      • Günther M.
      • Neuhhaus R.
      • Vandepapeliere P.
      • Vollmar J.
      • Lun A.
      • et al.
      Immunization with an adjuvant hepatitis B vaccine after liver transplantation for hepatitis B-related disease.
      ]. Unfortunately, the results could not be reproduced in another study [
      • Rosenau J.
      • Hooman N.
      • Rifai K.
      • Solga T.
      • Tillmann H.L.
      • Grzegowski E.
      • et al.
      Hepatitis B virus immunization with an adjuvant containing vaccine after liver transplantation for hepatitis B-related disease: failure of humoral and cellular immune response.
      ].
      Another approach is to use the biologically active molecules like granulocyte macrophage colony-stimulating factor as the adjuvant. A meta-analysis favors a significant effect in the antibody response rate and the achievement of an earlier seroconversion to the vaccine [
      • Cruciani M.
      • Mengoli C.
      • Serpelloni G.
      • Mazzi R.
      • Bosco O.
      • Malena M.
      Granulocyte macrophage colony-stimulating factor as an adjuvant for hepatitis B vaccination: a meta-analysis.
      ]. Other approaches include hepatitis B DNA vaccination with plasmid DNA encoding HBsAg [
      • Rottinghaus S.T.
      • Poland G.A.
      • Jacobson R.M.
      • Barr L.J.
      • Roy M.J.
      Hepatitis B DNA vaccine induces protective antibody responses in human non-responders to conventional vaccination.
      ], or administration of HBsAg-pulsed blood dendritic cells [
      • Fazle Akbar S.M.
      • Furukawa S.
      • Yoshida O.
      • Hiasa Y.
      • Horiike N.
      • Onji M.
      Induction of anti-HBs in HB vaccine nonresponders in vivo by hepatitis B surface antigen-pulsed blood dendritic cells.
      ], preliminary results in hepatitis B vaccine non-responders showed some promising results. More studies are needed to confirm these findings. The use of DNA immunization with oligodeoxynucleotides containing CpG motifs attempting to enhance the immune response, although successful in mice, was not effective in chimpanzees [
      • Payette P.J.
      • Ma X.
      • Weeratna R.D.
      • McCluski M.J.
      • Shapiro M.
      • Engle R.E.
      • et al.
      Testing of CpG-optimized protein and DNA vaccines against the hepatitis B virus in chimpanzees for immunogenicity and protection from challenge.
      ].

      3.2 Post-exposure settings

      The most thoroughly studied population for post-exposure prophylaxis is infants born to hepatitis B e antigen (HBeAg)-positive HBsAg carrier mothers. To bridge the gap between exposure to HBV and active production of anti-HBs induced by the hepatitis B vaccine, HBIG is given as soon as possible in these newborns no later than 24 h after birth. The efficacy of protecting from chronic HBV infection in these individuals is >90% [
      • Beasley R.P.
      • Hwang L.Y.
      • Lee G.C.Y.
      • Lan C.C.
      • Roan C.H.
      • Huang F.Y.
      • et al.
      Prevention of perinatally transmitted hepatitis B virus infection with hepatitis B immune globulin and hepatitis B vaccine.
      ,
      • Stevens C.E.
      • Taylor P.E.
      • Tong M.J.
      • Toy P.T.
      • Vyas G.N.
      • Nair P.V.
      • et al.
      Yeast-recombinant hepatitis B vaccine. Efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission.
      ,
      • Pongpipat D.
      • Suvatte V.
      • Assateerawatts A.
      Hepatitis B immunization in high risk neonates born from HBsAg positive mothers: comparison between plasma derived and recombinant DNA vaccine.
      ,
      • Lee C.Y.
      • Huang L.M.
      • Chang M.H.
      The protective efficacy of recombinant hepatitis B vaccine in newborn infants of hepatitis B e antigen-positive hepatitis B surface antigen carrier mothers.
      ,
      • Poovorawan Y.
      • Sanpavat S.
      • Pongpunlert W.
      • Chumdermpadetsuk S.
      • Sentrakul P.
      • Vandepapelière P.
      • et al.
      Long-trem efficacy of hepatitis B vaccine in infants born to hepatitis B e antigen-positive mothers.
      ,
      • Stevens C.E.
      • Toy P.T.
      • Taylor P.E.
      • Lee T.
      • Yip H.Y.
      Prospects for control of hepatitis B virus infection: implications of childhood vaccination and long-term protection.
      ,
      • Assateerawatt A.
      • Tanphaichitr V.S.
      • Suvatte V.
      • Yodthong S.
      Immunogenicity and efficacy of a recombinant DNA hepatitis B vaccine, GenHevac B Pasteur in high risk neonates, school children and healthy adults.
      ]. If HBIG is skipped, the efficacy is slightly lower, but can still be >83% [
      • Poovorawan Y.
      • Sanpavat S.
      • Pongpunlert W.
      • Chumdermpadetsuk S.
      • Sentrakul P.
      • Vandepapelière P.
      • et al.
      Long-trem efficacy of hepatitis B vaccine in infants born to hepatitis B e antigen-positive mothers.
      ,
      • Assateerawatt A.
      • Tanphaichitr V.S.
      • Suvatte V.
      • Yodthong S.
      Immunogenicity and efficacy of a recombinant DNA hepatitis B vaccine, GenHevac B Pasteur in high risk neonates, school children and healthy adults.
      ,
      • Poovorawan Y.
      • Sanpavat S.
      • Pongpunlert W.
      • Chumdermpadetsuk S.
      • Sentrakul P.
      • Safary A.
      Protective efficacy of a recombinant DNA hepatitis B vaccine in neonates of HBe antigen-positive mothers.
      ,
      • Milne A.
      • West D.J.
      • Chinh D.V.
      • Moyes C.D.
      • Poerschke G.
      Field evaluation of the efficacy and immunogenicity of recombinant hepatitis B vaccine without HBIG in newborn Vietnamese infants.
      ,
      • Lolekha S.
      • Warachit B.
      • Hirunyahote A.
      • Bowonkiratikachorn P.
      • West D.J.
      • Poerschke G.
      Protective efficacy of hepatitis B vaccine without HBIG in infants of HBeAg-positive carrier mothers in Thailand.
      ]. These findings form the basis in support for the use of vaccine alone in countries where pregnant women are not screened for HBsAg and HBeAg [
      • Poovorawan Y.
      • Theamboonlers A.
      • Vimolket T.
      • Sinlaparatsamee S.
      • Chaiear H.
      • Siraprasiri T.
      • et al.
      Impact of hepatitis B immunisation as part of the EPI.
      ]. Another important issue is the timely birth dose which should be given within 24 h after delivery, because a delay in this initial dose has been shown to lead to an increased risk of infection in children whose mothers are HBsAg carriers [
      • Marion S.A.
      • Tomm Pastore M.
      • Pi D.W.
      • Mathias R.G.
      Long-term follow-up of hepatitis B vaccine in infants of carrier mothers.
      ,
      • Ekra D.
      • Herbinger K.H.
      • Konates S.
      • Leblond A.
      • Fretz C.
      • Cilote V.
      • et al.
      A non-randomized vaccine effectiveness trial of accelerated infant hepatitis B immunization schedules with a first dose at birth or age 6 weeks in Côte d’Ivoire.
      ]. The heat stability of hepatitis B vaccines renders the administration of a timely birth dose feasible also in rural and remote areas [
      • Hipgrave D.B.
      • Tran T.N.
      • Huong V.M.
      • Dat D.T.
      • Nga N.T.
      • Long H.T.
      • et al.
      Immunogenicity of a locally produced hepatitis B vaccine with the birth dose stored outside the cold chain in rural Vietnam.
      ,
      • Otto B.F.
      • Suarnawa I.M.
      • Stewart T.
      • Nelson C.
      • Ruff T.A.
      • Widjava A.
      At-birth immunization against hepatitis B using a novel pre-filled immunization device stored outside the cold chain.
      ,
      • Hipgrave D.B.
      • Maynard J.E.
      • Biggs B.A.
      Improving birth dose coverage of hepatitis B vaccine.
      ,
      • Wang L.
      • Li J.
      • Chen H.
      • Li F.
      • Armstrong G.L.
      • Nelson C.
      • et al.
      Hepatitis B vaccination of newborn infants in rural China: evaluation of a village-based, out-of-cold-chain delivery strategy.
      ].
      Although HBeAg is a good marker of infectivity for us to judge whether to give or to skip administration of HBIG to the newborns of mothers who are HBsAg carriers [
      • Chen D.S.
      • Hsu N.H.M.
      • Sung J.L.
      • Hsu T.C.
      • Hsu S.T.
      • Kuo Y.T.
      • et al.
      A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
      ], despite hepatitis B vaccination, about 3% of infants born to HBeAg-negative HBsAg carrier mothers will still become persistently infected [
      • Hsu H.M.
      • Chen D.S.
      • Chuang C.H.
      • Lu J.C.F.
      • Jwo D.M.
      • Lee C.C.
      • et al.
      Efficacy of a mass hepatitis B vaccination program in Taiwan.
      ], indicating that defining infectivity by HBeAg in HBsAg carriers is not perfect. Actually, measurements of serum HBV DNA levels of HBsAg carrier mothers have been explored for the prediction of perinatal mother-to-infant transmission after immunoprophylaxis [
      • Lee S.D.
      • Lo K.J.
      • Wu J.C.
      • Tsai Y.T.
      • Wang J.Y.
      • Ting L.P.
      • et al.
      Prevention of maternal-infant hepatitis B virus transmission by immunization: the role of serum hepatitis B virus DNA.
      ,
      • Ip H.M.
      • Lelile P.N.
      • Wong V.C.
      • Kuhns M.C.
      • Reesink H.W.
      Prevention of hepatitis B virus carrier state in infants according to maternal serum levels of HBV DNA.
      ,
      • Söderström A.
      • Norkrans G.
      • Lindh M.
      Hepatitis B virus DNA during pregnancy and postpartum: aspects on vertical transmission.
      ,
      • Song Y.M.
      • Sung J.
      • Yang S.
      • Choe Y.H.
      • Chang Y.S.
      • Park W.S.
      Factors associated with immunoprophylaxis failure against vertical transmission of hepatitis B virus.
      ]. However, the results of these studies were confounded by hepatitis B immunoprophylaxis in the infants, and the roles of maternal serum HBV DNA and HBeAg in predicting infectivity were difficult to compare.
      In a cohort of 773 Taiwanese HBsAg-positive mothers and their infants in 1972–1980, it was documented that the maternal serum HBV DNA level is a stronger independent predictor of the infant’s persistent HBV infection than HBeAg [
      • Burk R.D.
      • Hwang L.Y.
      • Ho G.Y.
      • Shafritz D.A.
      • Beasley R.P.
      Outcome of perinatal hepatitis B virus exposure is dependent on maternal virus load.
      ]. In 22 HBeAg-positive HBsAg carrier women with undetectable serum HBV DNA, only 1(4.5%) of their infants became HBsAg carriers, in contrast to 82 HBV DNA-positive women’s infants in whom 53 (64.6%) became carriers. In 107 HBeAg-negative women, the persistent HBV infection in infants of 99 HBV DNA-negative and 8 HBV DNA-positive mothers was 5 (5.1%) and 3 (37.5%), respectively. The study also showed a linear relationship between maternal viral load and the likelihood of persistent HBV infection in their infants [
      • Burk R.D.
      • Hwang L.Y.
      • Ho G.Y.
      • Shafritz D.A.
      • Beasley R.P.
      Outcome of perinatal hepatitis B virus exposure is dependent on maternal virus load.
      ]. Hence, to decide whether HBIG should be used in newborns of HBsAg carrier mothers, serum HBV DNA rather than HBeAg appears to be more logical. However, further studies are needed [
      • Söderström A.
      • Norkrans G.
      • Lindh M.
      Hepatitis B virus DNA during pregnancy and postpartum: aspects on vertical transmission.
      ].
      Because maternal hepatitis B viral load is the most critical factor in causing HBV infection in the newborns even after passive-active immunoprophylaxis, by analogy with the situation in HIV infection [
      • Volmink J.
      • Siegfried N.L.
      • van der Merwe L.
      • Brocklehurst P.
      Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection.
      ], lowering the maternal viral load by antiviral therapy may reduce perinatal HBV infection. Indeed, in a pilot study [
      • Van Zonneveld M.
      • van Nunen A.B.
      • Niesters H.G.
      • de Man R.A.
      • Schalm S.W.
      • Janssen H.L.
      Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection.
      ], eight highly viremic HBsAg carrier mothers (serum HBV DNA ≥1.2 × 109 geq/ml) received lamivudine (150 mg per day) in the last month of pregnancy from week 34 on, one of 8 (12.5%) immunized infants became chronically infected. In the untreated historical controls, the chronic infection occurred in 7 of 25 (28%) children. Nevertheless, the data investigating whether addition of anti-HBV antivirals to near-term pregnant HBsAg carrier women will yield additional decrease of perinatal HBV infection are limited, and thus needs to be addressed further with randomized control trials. In addition, the issues of cost as well as safety in the mothers and newborns also require careful consideration.
      Preterm infants have decreased antibody response to hepatitis B vaccine [
      • Lau Y.L.
      • Tam A.Y.
      • Ng K.W.
      • Tsoi N.S.
      • Lam B.
      • Lam P.
      • et al.
      Response of preterm infants to hepatitis B vaccine.
      ], especially those with low birth weights (<1800 gm) [
      • Freitas da Motta M.S.
      • Mussi-Pinhata M.M.
      • Jorge S.M.
      • Tachibana Y.C.F.
      • Sandoval de Souza C.B.
      Immunogenicity of hepatitis B vaccine in preterm and full-term infants vaccinated within the first week of life.
      ,
      • Sood A.
      • Singh D.
      • Mehta S.
      • Midha V.
      • Kumar R.
      Response to hepatitis B vaccine in preterm babies.
      ] or premature gestation ages (<34 weeks) [
      • Sood A.
      • Singh D.
      • Mehta S.
      • Midha V.
      • Kumar R.
      Response to hepatitis B vaccine in preterm babies.
      ]. It has been recommended to defer the first dose of the vaccine in HBsAg-negative mother’s infants weighing <2000 gm until they reach 2000 gm, or alternatively, until one month old [
      • Patel D.M.
      • Butler J.
      • Feldman S.
      • Graves G.R.
      • Rhodes P.G.
      Immunogenicity of hepatitis B vaccine in healthy very low birth weight infants.
      ,
      • Saari T.N.
      • American Academy of Pediatrics Committee on Infectious Diseases
      Immunization of preferm and low birth weight infants.
      ].

      3.3 Duration of protection and the need of booster doses

      Vaccine-induced anti-HBs declines rapidly in the first year and then more gradually (reviewed in [
      • Mahoney F.J.
      • Kane M.
      Hepatitis B vaccine.
      ]). As time passes, the anti-HBs frequently becomes undetectable. Nevertheless, the vaccine-induced immunologic memory is maintained for at least 12 years despite the decline of anti-HBs [
      • West D.J.
      • Calandra G.B.
      Vaccine induced immunologic memory for hepatitis B surface antigen: implications for policy on booster vaccination.
      ]. Although, by testing humoral and cellular immunological parameters after a vaccine booster, we found a substantial proportion of fully vaccinated adolescents seem to lose immune memory conferred by hepatitis B vaccine given in infancy 15–18 years previously [
      • Lin C.Y.
      • Ni Y.H.
      • Chiang B.L.
      • Chen P.J.
      • Chang M.H.
      • Chang L.Y.
      • et al.
      Humoral and cellular immune responses to a hepatitis B vaccine booster 15–18 years after neonatal immunization.
      ], whether these findings represent susceptibility to HBV infection remains to be seen. Actually, a booster vaccination is not needed for at least 20 years in Taiwan, because surveillance did not reveal any increase of acute hepatitis B [
      • Chen D.S.
      Long-term protection of hepatitis B vaccine: lessons from Alaskan experience after 15 years.
      ] or chronic HBV infection [
      • Ni Y.H.
      • Huang L.M.
      • Chang M.H.
      • Yen C.J.
      • Lu C.Y.
      • You S.L.
      • et al.
      Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
      ] in adolescents vaccinated 20 years ago. For endemic areas like Taiwan where the primary goal of hepatitis B immunization is to prevent hepatitis B chronic carriage in infancy [
      • Chen D.S.
      • Hsu N.H.M.
      • Sung J.L.
      • Hsu T.C.
      • Hsu S.T.
      • Kuo Y.T.
      • et al.
      A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
      ], even if the immunity conferred by the vaccine given in early childhood disappears, when the unprotected vaccine contract HBV infection in adulthood, the risk of becoming HBsAg carriers is far lower [
      • Edmunds W.J.
      • Medley G.F.
      • Nokes D.J.
      • Hall A.J.
      • Whittle H.C.
      The influence of age on the development of the hepatitis B carrier state.
      ]. In this case, the primary goal has already been achieved then. A global universal infant immunization will postpone HBV infection in any given population to an older age when HBV infection will result in much less chronic HBsAg carriage worldwide. This will be a significant step towards the eradication of HBV infection. Nonetheless, after chronic HBV infection is well-controlled, the need of preventing acute hepatitis B in young adults will become evident. Therefore prolonged follow-up and surveillance of the vaccinees who received immunization in early childhood should continue. A booster vaccination will be considered only when the cohort start to have clinically significant acute hepatitis B. So far, in the endemic areas for hepatitis B, breakthrough HBV infections in the vaccinees who received the immunization in infancy occur infrequently, ranging from 0.008% to 0.19% per year (Table 1) [
      • Lin Y.C.
      • Chang M.H.
      • Ni Y.H.
      • Hsu H.Y.
      • Chen D.S.
      Long-term immunogenicity and efficacy of universal hepatitis B virus vaccination in Taiwan.
      ,
      • Boxall E.H.
      • Sira J.A.
      • El-Shuhkri N.
      • Kelly D.A.
      Long-term persistence of immunity to hepatitis B after vaccination during infancy in a country where endemicity is low.
      ,
      • Yuen M.F.
      • Lim W.L.
      • Chan A.O.O.
      • Wong D.K.H.
      • Sum S.S.M.
      • Lai C.L.
      18-year follow-up study of a prospective randomized trial of hepatitis B vaccinations without booster doses in children.
      ,
      • McMahon B.J.
      • Bruden D.L.
      • Peterson K.M.
      • Bulkow L.R.
      • Parkinson A.J.
      • Nainan O.
      • et al.
      Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up.
      ,
      • Dentiger C.M.
      • McMahon B.J.
      • Butler J.C.
      • Dunaway C.E.
      • Zanis C.L.
      • Bulkow L.R.
      • et al.
      Persistence of antibody to hepatitis B and protection from disease among Alaskan natives immunized at birth.
      ,
      • Zanetti A.R.
      • Mariano A.
      • Romanò L.
      • D’Amelio R.
      • Chironna M.
      • Coppola R.C.
      • et al.
      Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study.
      ]. In the rare cases of these breakthrough infections, they are subclinical and rarely become chronic.
      Table 1Breakthrough hepatitis B virus infections in the vaccinees who received hepatitis B immunization in childhood.
      Author [Ref.]/year/countryNo. of subjects studiedNo. with HBV infection
      The infections were asymptomatic and rarely became chronic.
      Observation period (years)Average annual incidence (%)
      Lin et al.
      • Lin Y.C.
      • Chang M.H.
      • Ni Y.H.
      • Hsu H.Y.
      • Chen D.S.
      Long-term immunogenicity and efficacy of universal hepatitis B virus vaccination in Taiwan.
      /2003/Taiwan
      12001170.13
      Boxall et al.
      • Boxall E.H.
      • Sira J.A.
      • El-Shuhkri N.
      • Kelly D.A.
      Long-term persistence of immunity to hepatitis B after vaccination during infancy in a country where endemicity is low.
      /2004/UK, Asian
      64115.10.10
      52111.80.16
      Yuan et al.
      • Yuen M.F.
      • Lim W.L.
      • Chan A.O.O.
      • Wong D.K.H.
      • Sum S.S.M.
      • Lai C.L.
      18-year follow-up study of a prospective randomized trial of hepatitis B vaccinations without booster doses in children.
      /2004/China, Hong Kong
      883180.19
      McMahon et al.
      • McMahon B.J.
      • Bruden D.L.
      • Peterson K.M.
      • Bulkow L.R.
      • Parkinson A.J.
      • Nainan O.
      • et al.
      Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up.
      /2005/US, Alaska
      157816150.08
      Dentinger et al.
      • Dentiger C.M.
      • McMahon B.J.
      • Butler J.C.
      • Dunaway C.E.
      • Zanis C.L.
      • Bulkow L.R.
      • et al.
      Persistence of antibody to hepatitis B and protection from disease among Alaskan natives immunized at birth.
      /2005/US, Alaska
      3346100.18
      Zanetti et al.
      • Zanetti A.R.
      • Mariano A.
      • Romanò L.
      • D’Amelio R.
      • Chironna M.
      • Coppola R.C.
      • et al.
      Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study.
      /2005/Italy
      1212110.60.008
      HBV: hepatitis B virus.
      a The infections were asymptomatic and rarely became chronic.

      4. Hepatitis B mass vaccination

      After the hepatitis B vaccine became available, it was found that targeting at populations at risk of HBV infection, such as homosexuals, sex workers, drug abusers or teenagers was not easy [
      • Alter M.J.
      • Hadler S.C.
      • Margolis H.S.
      • Alexander W.J.
      • Hu P.Y.
      • Judson F.N.
      • et al.
      The changing epidemiology of hepatitis B in the United States. Need for alternative vaccination strategies.
      ]. On the other hand, universal vaccination against HBV in newborns was found to be easier and cost-effective [
      • Arevalo J.A.
      • Washington A.E.
      Cost-effectiveness of prenatal screening and immunization for hepatitis B virus.
      ,
      • Van Damme D.
      • Kane M.
      • Meheus A.
      Integration of hepatitis B vaccination into national immunisation programmes.
      ]. Incorporation of hepatitis B vaccine into the routine Expanded Program on Immunization (EPI) of infants has been shown to be feasible and practical [
      • Poovorawan Y.
      • Theamboonlers A.
      • Vimolket T.
      • Sinlaparatsamee S.
      • Chaiear H.
      • Siraprasiri T.
      • et al.
      Impact of hepatitis B immunisation as part of the EPI.
      ,
      • Anonymous
      Hepatitis B vaccine in the expanded programme of immunisation: the Gambian experience.
      ,
      • Ruff R.A.
      • Gertig D.M.
      • Otto B.F.
      • Gust I.D.
      • Sutano A.
      • Soewarso T.I.
      • et al.
      Lombok hepatitis B model immunization project: towards universal hepatitis B immunization in Indonesia.
      ]. As of 2007, according to World Health Organization (WHO) 71 (89%) of the 193 member states had initiated a hepatitis B vaccination program. The global coverage of completing three doses of hepatitis B vaccine was 65% on average, ranging from 89% in the American Region to 28% in the Southeast Asian Region [http://www.who.int/immunization_monitoring/data/en/].
      Due to the fact that chronic HBsAg carriage has been shown to correlate with the age when HBV infection occurs, the younger the age, the higher the chronicity [
      • Edmunds W.J.
      • Medley G.F.
      • Nokes D.J.
      • Hall A.J.
      • Whittle H.C.
      The influence of age on the development of the hepatitis B carrier state.
      ], and because of the very high prevalence of chronic HBV infection in Taiwan as well as the extremely heavy disease burden caused by HBV [
      • Chen D.S.
      Hepatitis B virus infection, its sequelae, and prevention in Taiwan.
      ], a national hepatitis B vaccination program was launched in 1984 [
      • Chen D.S.
      • Hsu N.H.M.
      • Sung J.L.
      • Hsu T.C.
      • Hsu S.T.
      • Kuo Y.T.
      • et al.
      A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
      ], soon after the hepatitis B vaccines became available. As this is the earliest nationwide hepatitis B mass vaccination in the world, much important information can be obtained from it and I will use Taiwan’s experience to elucidate some of the issues in this review. Briefly, pregnant women were screened for HBsAg and then HBeAg. If they were positive for HBeAg, their newborn infants received HBIG immediately after birth, followed by hepatitis B vaccine given within the first week of life. In more than 90% of infants, the first dose was given in the first or second day after birth. In those carrier mothers who were negative for HBeAg, the infants receive hepatitis B vaccines only, so did infants of non-carrier mothers. The program was carefully planned and has been supported strongly by Taiwan’s Government [
      • Chen D.S.
      • Hsu N.H.M.
      • Sung J.L.
      • Hsu T.C.
      • Hsu S.T.
      • Kuo Y.T.
      • et al.
      A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
      ]. Mass immunization against hepatitis B is very well accepted by the people and the coverage rate of vaccination in infants is >96% [
      • Ni Y.H.
      • Huang L.M.
      • Chang M.H.
      • Yen C.J.
      • Lu C.Y.
      • You S.L.
      • et al.
      Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
      ].
      Worldwide, there are four different strategies of universal hepatitis B vaccination in newborns (Table 2). The most simple one is to give the vaccine to all newborns regardless of the maternal HBV status. Because screening of pregnant women is not necessary and HBIG is skipped in newborns, this strategy incurs the lowest costs. However, the efficacy may be jeopardized [
      • Poovorawan Y.
      • Sanpavat S.
      • Pongpunlert W.
      • Chumdermpadetsuk S.
      • Sentrakul P.
      • Vandepapelière P.
      • et al.
      Long-trem efficacy of hepatitis B vaccine in infants born to hepatitis B e antigen-positive mothers.
      ,
      • Assateerawatt A.
      • Tanphaichitr V.S.
      • Suvatte V.
      • Yodthong S.
      Immunogenicity and efficacy of a recombinant DNA hepatitis B vaccine, GenHevac B Pasteur in high risk neonates, school children and healthy adults.
      ,
      • Poovorawan Y.
      • Sanpavat S.
      • Pongpunlert W.
      • Chumdermpadetsuk S.
      • Sentrakul P.
      • Safary A.
      Protective efficacy of a recombinant DNA hepatitis B vaccine in neonates of HBe antigen-positive mothers.
      ,
      • Milne A.
      • West D.J.
      • Chinh D.V.
      • Moyes C.D.
      • Poerschke G.
      Field evaluation of the efficacy and immunogenicity of recombinant hepatitis B vaccine without HBIG in newborn Vietnamese infants.
      ,
      • Lolekha S.
      • Warachit B.
      • Hirunyahote A.
      • Bowonkiratikachorn P.
      • West D.J.
      • Poerschke G.
      Protective efficacy of hepatitis B vaccine without HBIG in infants of HBeAg-positive carrier mothers in Thailand.
      ,
      • Hsu H.M.
      • Lu C.F.
      • Lee S.C.
      • Lin S.R.
      • Chen D.S.
      Seroepidemiologic survey for hepatitis B virus infection in Taiwan: the effect of hepatitis B mass immunization.
      ]. The most expensive yet most efficacious strategy is to give hepatitis B vaccine to all newborns, and to screen the pregnant women and add on HBIG to the newborns if the mother is positive for HBsAg, regardless of the HBeAg status. Each country can choose its own strategy depending on its own needs after considering epidemiology, disease burden, readiness of the public health system and economic constraint. Any approach in implementing hepatitis B vaccination will help to control hepatitis B in the country.
      Table 2Four different strategies of universal hepatitis B immunization in infants.
      Modified from Chang [120].
      Maternal screeningInfants receiveEfficacyCostExample
      VaccineHBIG
      Yes (HBsAg and then HBeAg)YesHBeAg-positive mothers’ infants onlyHigherHigherTaiwan
      Yes (HBsAg only)YesAll HBsAg-positive mothers’ infantsHighestHighestUS
      Yes (HBeAg only)YesHBeAg-positive mothers’ infants only (2 doses)HighHighestJapan
      Before 1995.
      NoYesNoModestLowThailand
      HBsAg: hepatitis B surface antigen.
      HBeAg: hepatitis B e antigen.
      HBIG: hepatitis B immune globulin.
      a Modified from Chang
      • Chang M.H.
      Hepatitis B virus infection.
      .
      b Before 1995.

      4.1 Decrease of chronic HBsAg carriage

      After implementation of the universal hepatitis B vaccination in infants, seroepidemiologic studies soon reveal a steady and remarkable decrease of chronic HBsAg carrier rate in children, as shown in serial surveys in Taipei City in 1989, 1994, 1999 and 2004 (Fig. 1) [
      • Ni Y.H.
      • Huang L.M.
      • Chang M.H.
      • Yen C.J.
      • Lu C.Y.
      • You S.L.
      • et al.
      Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
      ]. The decrease has been confirmed in other parts of Taiwan (Table 3). Once hepatitis B vaccination is implemented in early childhood, there is always an evident effectiveness of protecting from chronic HBV infection (Table 3). In less endemic areas, the post-vaccination HBsAg carrier rate can even reach zero, harbingering the elimination and eventual eradication of HBV in the population.
      Figure thumbnail gr1
      Fig. 1Prevalence of hepatitis B surface antigen (HBsAg) in healthy children in Taipei from 1984 to 2004
      [
      • Ni Y.H.
      • Huang L.M.
      • Chang M.H.
      • Yen C.J.
      • Lu C.Y.
      • You S.L.
      • et al.
      Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
      ]
      . The mass hepatitis B vaccination started in July 1984.
      Table 3Effectiveness of protecting from HBsAg carriage after hepatitis B immunization.
      Reference list will be provided on request.
      CountryHBsAg (%)Efficacy (%)
      BeforeAfter
      China, rural14.61.490.4
      China (Shanghai)110.6394.3
      Egypt (Alexandria)2.20.863.6
      Gambia120.992.5
      Indonesia (Lombok)6.21.461.1
      Italy (Afragola)13.40.993.3
      Japan (Iwate)0.90.0396.7
       (Shizuoka)0.30.0390.0
      Korea7.50.3894.9
      Malaysia2.50.484.0
      Micronesia122.975.8
      Polynesia6.50.789.2
      Saipan90.594.4
      Samoa70.592.9
      Saudi Arabia6.70.395.5
      Senegal19289.5
      Singapore4.10100
      South Africa12.83.076.6
      Taiwan (Taipei)100.793.0
      (Hualien)9.31.979.6
      (Taichung)141.291.4
      Thailand4.30.783.7
      US (Alaska)160100
      a Reference list will be provided on request.

      4.2 Decrease of diseases associated with acute HBV infection

      After universal hepatitis B vaccination in infants, the mortality rate of fulminant hepatitis in infants decreases remarkably. In our study, fulminant hepatitis in infants reduced 70% (from 5.36/105 in pre-vaccination era to 1.71/105 post-vaccination) [
      • Kao J.H.
      • Hsu H.M.
      • Shau W.Y.
      • Chang M.H.
      • Chen D.S.
      Universal hepatitis B vaccination and the decreased mortality from fulminant hepatitis in infants in Taiwan.
      ]. In addition, fulminant hepatitis B in children older than one year of age is then nearly wiped out [
      • Chen H.L.
      • Chang C.J.
      • Kong M.S.
      • Huang F.C.
      • Lee H.C.
      • Lin C.C.
      • et al.
      Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination.
      ]. In Italy where HBV is intermediately endemic and universal vaccination of infants and adolescents was launched in 1991, besides decrease of chronic HBV infection, the incidence of acute hepatitis B decreased 50-fold, from 1/105 in pre-vaccination era to 0.02/105 post-vaccination [
      • Mele A.
      • Tosti M.E.
      • Mariano A.
      • Pizzuti R.
      • Ferro A.
      • Borrini B.
      • et al.
      Acute hepatitis B 14 years after the implementation of universal vaccination in Italy: areas of improvement and emerging challenges.
      ]. Nevertheless, it was found that HBV infection through household contacts of chronic HBsAg carriers, injection drug use, and iatrogenic procedures still needed to be interrupted to eradicate the residual HBV infection in the country. An anticipated bonus after universal hepatitis B vaccination in Italy is the marked decrease of acute hepatitis D infection [
      • Mele A.
      • Mariano A.
      • Tosti M.E.
      • Stroffolini T.
      • Pizzuti R.
      • Gallo G.
      • et al.
      Acute hepatitis delta virus infection in Italy: incidence and risk factors after the introduction of universal anti-hepatitis B vaccination campaign.
      ]. In Singapore, a similar decrease of acute hepatitis B was also noted after hepatitis B vaccination [
      • Goh K.T.
      Prevention and control of hepatitis B virus infection in Singapore.
      ].

      4.3 Decrease of diseases associated with chronic HBV infection

      After hepatitis B vaccination in South Africa, a hospital-based study clearly demonstrated a sharp decline in the incidence of HBV-associated membranous nephropathy [
      • Bhimma R.
      • Coovadia H.M.
      • Adhikari M.
      • Connolly C.A.
      The impact of hepatitis B virus vaccine on the incidence of hepatitis B virus-associated membranous nephropathy.
      ]. Another hospital-based study from China also revealed that the incidence of HBV-associated glomerulonephritis decreased steadily after nationwide hepatitis B vaccination program [
      • Xu H.
      • Sun L.
      • Zhou L.J.
      • Sheng F.Y.
      • Guo Y.Q.
      The effect of hepatitis B vaccination on the incidence of childhood HBV-associated nephritis.
      ].

      4.4 Decrease of hepatocellular carcinoma

      In endemic areas of chronic HBV infection, HCC is always prevalent and occurs usually after middle age [
      • Margolis H.S.
      Fact sheets for candidate diseases for elimination or eradication. Hepatitis B virus infection.
      ,
      • Chen D.S.
      Hepatitis B virus infection, its sequelae, and prevention in Taiwan.
      ]. If one wants to see the impact of hepatitis B vaccination on the occurrence of HCC, one would have to wait for 4–5 decades after the vaccination. Fortunately, we found a proxy to serve this purpose. In endemic areas of HBV, HCC in children can be seen occasionally, and is almost always related to chronic HBV infection which was transmitted to the patient from their mothers [
      • Chang M.H.
      • Chen D.S.
      • Hsu H.C.
      • Hsu H.Y.
      • Lee C.Y.
      Maternal transmission of hepatitis B virus in childhood hepatocellular carcinoma.
      ]. To investigate whether or not universal hepatitis B vaccination in newborns has impacts on the occurrence of HCC in Taiwan, we studied the incidence of HCC in children 6–9 years of age. It declined 4-fold from 0.52/105 in the cohort born before implementation of the universal vaccination program to 0.13/105 in those born after the program [
      • Chang M.H.
      • Chen C.J.
      • Lai M.S.
      • Hsu H.M.
      • Wu T.C.
      • Kong M.S.
      • et al.
      Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children.
      ]. Another study that included Taiwanese children 0–9 years of age also reached the same conclusions [
      • Lee C.L.
      • Ko Y.C.
      Hepatitis B vaccination and hepatocellular carcinoma in Taiwan.
      ].After some time, the studies were extended to children of 14 years of age, and the decrease of HCC was again evident [
      • Lee C.L.
      • Hsieh K.S.
      • Ko Y.C.
      Trends in the incidence of hepatocellular carcinoma in boys and girls in Taiwan after large-scale hepatitis B vaccination.
      ,
      • Chang M.H.
      • Chen T.H.
      • Hsu H.M.
      • Wu T.C.
      • Kong M.S.
      • Liang D.C.
      • et al.
      Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems.
      ]. Our most recent observations in adolescents (up to 19 years old) have shown that the effect has extended from childhood to early adulthood (unpublished observations). A cohort study from Korea suggested that hepatitis B vaccination in men can reduce the risk of HCC [
      • Lee M.S.
      • Kim D.H.
      • Kim H.
      • Lee H.S.
      • Kim C.Y.
      • Park T.S.
      • et al.
      Hepatitis B vaccination and reduced risk of primary liver cancer among male adults: a cohort study in Korea.
      ]. After large-scale hepatitis B vaccination, a similar trend of decrease in the incidence of HCC has also been reported form Singapore [
      • Goh K.T.
      Prevention and control of hepatitis B virus infection in Singapore.
      ], China [
      • Li R.C.
      • Yang J.Y.
      • Gong J.
      • Li Y.P.
      • Huang Z.N.
      • Fang K.X.
      • et al.
      Efficacy of hepatitis B vaccination on hepatitis B prevention and on hepatocellular carcinoma.
      ] and Saudi Arabia [
      • Madani T.A.
      Trend in incidence of hepatitis B virus infection during a decade of universal childhood hepatitis B vaccination in Saudi Arabia.
      ]. However, whether the decrease of HCC in these countries was associated with hepatitis B vaccination could not be ascertained, because the decrease was also seen in adult populations who were not vaccinated.

      5. Safety and adverse events

      To date, more than one billion doses of plasma-derived or recombinant DNA vaccines have been used, and the safety records of the hepatitis B vaccines are excellent. Besides reactogenicities that include mild fever in 1–6% of vaccinees and soreness at the injection site in 3–30%, there is a remote risk of anaphylaxis (1.1 per million doses) [
      • Bohlke K.
      • Davis R.L.
      • Marcy S.M.
      • Braun M.M.
      • DeStefano F.
      • Black S.B.
      • et al.
      Risk of anaphylaxis after vaccination of children and adolescents.
      ]. In addition, the following outcomes have been claimed to be the adverse reactions after hepatitis B vaccination, namely, chronic fatigue syndrome, multiple sclerosis, sudden infant death syndrome, rheumatoid arthritis, leukemia, macrophagic myofasciitis, type I diabetes, vasculitis, immune thrombocytopenic purpura, central retinal vein occlusion, lichenoid, lichen planus, cutaneous lupus, Guillain–Barré syndrome, transverse myelitis, optic neuritis, fluctuating hearing loss, hair loss, etc. Many of them are rare and occur also in the absence of hepatitis B vaccination. The causal association of these disorders with the vaccination is not established (reviewed in [
      • Duclos P.
      Safety of immunization and adverse events following vaccination against hepatitis B.
      ] recently). A similar situation also occurred in alleged suspicion of ethyl mercury-containing vaccine preservative – thiomersal in causing adverse reactions. Actually thiomersal has long been a safe and effective preservative [
      • Duclos P.
      Safety of immunization and adverse events following vaccination against hepatitis B.
      ]. Nevertheless, to avoid laborious yet unproductive defence against repeated alleged accusations, many pharmaceutical companies have avoided using it in their vaccines. In making decisions, it should be borne in mind that the benefit of hepatitis B vaccination far outweighs the alleged adverse reactions.

      6. Vaccine escape mutants

      Under immune pressure of hepatitis B immunization, especially when HBIG is combined, HBV with mutations in the a determinant can be selected [
      • Carman W.F.
      • Zanetti A.R.
      • Karayiannis P.
      • Waters J.
      • Manzillo G.
      • Tanzi E.
      • et al.
      Vaccine-induced escape mutant of hepatitis B virus.
      ]. The most common is a glycine to arginine change at aminoacid position 145. In Taiwan, the baseline prevalence of the a mutants was 7.8% in HBsAg carrier children, and was kept around 20% among HBsAg carrier children in the first 15 years of the universal mass vaccination program [
      • Hsu H.Y.
      • Chang M.H.
      • Ni Y.H.
      • Chen H.L.
      Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination program in Taiwan.
      ]. In the last 10 years, there has been no steady increase of the vaccine escape HBV mutants in Taiwanese carrier children who failed in the mass vaccination program, and there has been no evidence of the spread of this virus, likely because of the weakness of the mutant virus [
      • Kalinia T.
      • Iwanski A.
      • Will H.
      • Sterneck M.
      Deficiency in virion secretion and decreased stability of the hepatitis B immune escape mutant G145R.
      ]. Despite the increased percentage of surface gene mutants after mass hepatitis B vaccination, the actual number of children infected with this mutant is small and is not increasing [
      • Hsu H.Y.
      • Chang M.H.
      • Ni Y.H.
      • Chen H.L.
      Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination program in Taiwan.
      ]. The results in Italy also concurred with the same conclusions [
      • Mele A.
      • Tancredi F.
      • Romano L.
      • Giuseppone A.
      • Coluci M.
      • Sangiulo A.
      • et al.
      Effectiveness of hepatitis B vaccination in babies born to hepatitis B surface antigen-positive mothers in Italy.
      ]. Therefore, the presence of vaccine escape mutants does not seem to threaten the ongoing hepatitis B control strategies in Taiwan and Italy, and perhaps, worldwide. Worthy of note is the fact that the current hepatitis B vaccines can protect chimpanzees from the infection with this a mutant virus [
      • Ogata N.
      • Cote P.J.
      • Zanetti A.R.
      • Miller R.H.
      • Shapiro M.
      • Gerin J.
      • et al.
      Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus.
      ]. Hence, the currently available hepatitis B vaccines can be continued.

      7. Challenges that need to be solved to expand hepatitis B mass vaccination

      Although the hepatitis B vaccine has been available since 1982, and more than one billion people have been vaccinated, there are still many people who are not immunized. According to WHO, in 2006, 40% of infants worldwide had not yet received three doses of hepatitis B vaccine. The causes of failing to offer large-scale hepatitis B vaccination in each country are complicated.

      7.1 Improving infrastructure of public health delivery system

      In the absence of an effective system of public health delivery, basic regular immunization for infants is impossible, not to mention hepatitis B immunization. Usually such countries are poor and have limited resources for creating and maintaining regular operational facilities for public health. The well-trained public health personnel necessary to carry on the immunization program are also inadequate or even lacking. And thus, it is of vital importance to support these countries, so that vaccinations can be given as much as possible, including the hepatitis B vaccine. Integration of hepatitis B vaccination to the EPI will facilitate the vaccination in children [
      • Poovorawan Y.
      • Theamboonlers A.
      • Vimolket T.
      • Sinlaparatsamee S.
      • Chaiear H.
      • Siraprasiri T.
      • et al.
      Impact of hepatitis B immunisation as part of the EPI.
      ,
      • Anonymous
      Hepatitis B vaccine in the expanded programme of immunisation: the Gambian experience.
      ,
      • Ruff R.A.
      • Gertig D.M.
      • Otto B.F.
      • Gust I.D.
      • Sutano A.
      • Soewarso T.I.
      • et al.
      Lombok hepatitis B model immunization project: towards universal hepatitis B immunization in Indonesia.
      ].
      Besides the constant endeavors on behalf of governments and WHO, efforts from non-government organizations are also needed. Among them, Global Alliance on Vaccines and Immunization (GAVI) is most noteworthy. The GAVI was founded in 2000, and is a global coalition of international organizations, philanthropic foundations, private sectors including vaccine industry representatives as well as research and public health institutions [
      • Namgyal P.
      Impact of hepatitis B immunization, Europe and worldwide.
      ]. It targets the world’s poorest countries to help improve child health by extending the reach and quality of immunization coverage with strengthened health services. The hepatitis B vaccine has been included in the GAVI since 2000. Millions of children since then have received hepatitis B vaccine through the help of GAVI. In 2004, the coverage rate was 37.9% in 52 of the 75 counties eligible for GAVI support. By the end of 2008, 71 countries are expected to have introduced the hepatitis B vaccine [Hepatitis B. GAVI Alliance. www.gavialliance.org].

      7.2 Public education

      The public should be educated about the importance and necessity of hepatitis B prevention by vaccination. In Taiwan, we dedicated a lot of time and efforts in public education for nearly three years prior to the implementation of our universal vaccination program in 1984 [
      • Chen D.S.
      • Hsu N.H.M.
      • Sung J.L.
      • Hsu T.C.
      • Hsu S.T.
      • Kuo Y.T.
      • et al.
      A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
      ]. Because of the importance of giving immunization immediately after birth, young people, especially women of reproductive age, are targeted for this education. At the same time, education of medical personnel is also necessary, because iatrogenic HBV infections are an important mode of HBV transmission. The key role of education can be seen in the Italian experience. Despite the success of universal vaccination against HBV since 1991, household contacts of HBsAg carriers, injection drug use, unprotected sexual behaviors and invasive medical procedures are still evident in transmitting HBV [
      • Mele A.
      • Tosti M.E.
      • Mariano A.
      • Pizzuti R.
      • Ferro A.
      • Borrini B.
      • et al.
      Acute hepatitis B 14 years after the implementation of universal vaccination in Italy: areas of improvement and emerging challenges.
      ].

      8. Strategies towards eradication of hepatitis B

      As depicted in Fig. 2, HBV infection has three components, an infectious source, a susceptible host and an established route of transmission [
      • Kao J.H.
      • Chen D.S.
      Global control of hepatitis B virus infection.
      ]. Because humans are the only reservoir of HBV, it is not impossible that a comprehensive control can eventually lead to the eradication of the virus. To begin with, the existing HBV carriers can now be treated effectively [
      • Hoofnagle J.H.
      • Doo E.
      • Liang T.J.
      • Fleischer R.
      • Lok A.S.F.
      Management of hepatitis B: Summary of a clinical research workshop.
      ] and viral load can decrease to undetectable levels, so that infection does not spread rampantly. However, prolonged use of current nucleos(t)ide analogs against HBV still poses the problem of viral resistance and the cost of long-term treatment is still high [
      • Hoofnagle J.H.
      • Doo E.
      • Liang T.J.
      • Fleischer R.
      • Lok A.S.F.
      Management of hepatitis B: Summary of a clinical research workshop.
      ]. Another important strategy is to interrupt the transmission route which can be reduced after education of the public and medical personnel as mentioned above although changes in high-risk human behaviors are often difficult. The most effective strategy is to immunize all susceptible individuals with the hepatitis B vaccine, especially children [
      • Margolis H.S.
      Fact sheets for candidate diseases for elimination or eradication. Hepatitis B virus infection.
      ,
      • Kao J.H.
      • Chen D.S.
      Global control of hepatitis B virus infection.
      ].
      Figure thumbnail gr2
      Fig. 2Components of hepatitis B virus (HBV) infection and the relation to eradication of the infection.
      In the modern globalized world, international travel and immigration are frequent, and adoption of children from HBV high-endemicity countries is not uncommon. Countries where the incidence of HBV infection is low should seriously consider shifting their immunization policy from targeting at-risk population to universal childhood hepatitis B vaccination [
      • Zuckerman J.
      • Van Hattum J.
      • Cafferkey M.
      • Gjorup I.
      • Hoel T.
      • Rummukainen M.L.
      • et al.
      Should hepatitis B vaccination be introduced into childhood immunization programmes in northern Europe?.
      ,
      • Pollard A.J.
      Hepatitis B vaccination. The BMA adds its voice to the call for universal childhood immunisation in the UK.
      ,
      • Anonymous
      Hepatitis B as of July 2006, Japan.
      ]. Universal hepatitis B vaccination in childhood can prevent not only chronic HBV infection in high endemic areas, but also acute HBV infection in low endemic areas. Therefore, it should be recommended for all countries, regardless of HBV endemicity [
      • Kao J.H.
      • Chen D.S.
      Universal hepatitis B vaccination: killing two birds with one stone.
      ]. The combined efforts of universal vaccination, antiviral treatment and interruption of transmission make elimination of HBV infection plausible and eventually may result in the eradication of HBV. To reach this goal, all the efforts need to be supported adequately, and a long-term commitment from each government, WHO or non-government organizations is a must. The support should sustain and overcome the existing backlog of HBV carriers in the population. The goal of eradicating HBV is plausible, but every endeavor has to be pursued to make it become a reality.

      Acknowledgment

      This work was supported in part by Taiwan’s Department of Health and National Science Council.

      References

        • Chen D.S.
        From hepatitis to hepatoma: lessons from type B viral hepatitis.
        Science. 1993; 262: 369-370
        • Margolis H.S.
        Fact sheets for candidate diseases for elimination or eradication. Hepatitis B virus infection.
        Bull World Health Organ. 1998; 76: 152-153
        • Kao J.H.
        • Chen D.S.
        Global control of hepatitis B virus infection.
        Lancet Infect Dis. 2002; 2: 395-403
        • Fenner F.
        Candidate viral diseases for elimination or eradication.
        Bull World Health Organ. 1998; 76: 68-70
        • Hoofnagle J.H.
        • Doo E.
        • Liang T.J.
        • Fleischer R.
        • Lok A.S.F.
        Management of hepatitis B: Summary of a clinical research workshop.
        Hepatology. 2007; 45: 1056-1075
        • Szmuness W.
        • Stevens C.E.
        • Harley E.J.
        • Zang E.A.
        • Oleszko W.R.
        • William D.C.
        • et al.
        Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States.
        N Engl J Med. 1980; 303: 833-841
        • Maupas P.
        • Chiron P.
        • Barin F.
        • Coursaget P.
        • Goudeau A.
        • Perrin J.
        • et al.
        Efficacy of hepatitis B vaccine in prevention of early HBsAg carrier state in children. Controlled trial in an endemic area (Senegal).
        Lancet. 1981; 1: 289-292
        • Beasley R.P.
        • Hwang L.Y.
        • Lee G.C.Y.
        • Lan C.C.
        • Roan C.H.
        • Huang F.Y.
        • et al.
        Prevention of perinatally transmitted hepatitis B virus infection with hepatitis B immune globulin and hepatitis B vaccine.
        Lancet. 1983; 2: 1099-1102
        • Barre-Sinoussi F.
        • Chermann J.C.
        • Rey F.
        • Nugeyre M.T.
        • Chamaret S.
        • Gruest J.
        • et al.
        Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS).
        Science. 1983; 220: 868-871
        • Ni Y.H.
        • Huang L.M.
        • Chang M.H.
        • Yen C.J.
        • Lu C.Y.
        • You S.L.
        • et al.
        Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
        Gastroenterology. 2007; 132: 1287-1293
        • Shapira M.Y.
        • Zeira E.
        • Adler R.
        • Shouval D.
        Rapid seroprotection against hepatitis B following the first dose of a pre-S1/pre-S2/S vaccine.
        J Hepatol. 2001; 34: 123-127
        • Young M.D.
        • Schneider D.L.
        • Zuckerman A.J.
        • Du W.
        • Dickson B.
        • Maddrey W.C.
        • et al.
        Adult hepatitis B vaccination using a novel triple antigen recombinant vaccine.
        Hepatology. 2001; 34: 372-376
        • Kundi M.
        New hepatitis B vaccine formulated with an improved adjuvant system.
        Expert Rev Vaccines. 2007; 6: 133-140
        • Pichichero M.E.
        • Bernstein H.
        • Blatter M.M.
        • Schuerman L.
        • Cheuvart B.
        • Holmes S.J.
        • et al.
        Immunogenitity and safety of a combination diphtheria, tetanus toxoid, acellular pertussis, hepatitis B, and inactivated poliovirus vaccine coadministered with a 7-valent pneumococcal conjugate vaccine and a Haemophilus influenzae type b conjugate vaccine.
        J Pediatr. 2007; 151: 43-49
        • Ortega-Barria E.
        • Kanra G.
        • Leroux G.
        • Bravo L.
        • Safary A.
        • Lefevre I.
        • et al.
        The immunogenicity and reactogenicity of DTPw-HBV/Hib 2.5 combination vaccine: results from four phase III multicenter trials across five continents.
        Vaccine. 2007; 25: 8432-8440
        • Mallet E.
        • Belohradsky B.H.
        • Lagos R.
        • Gothefors L.
        • Camier P.
        • Carriere J.P.
        • et al.
        A liquid hexavalent combined vaccine against diphtheria, tetanus, pertussis, poliomyelitis, Hemophilus infuluenzae type B and hepatitis B: review of immunogenicity and safety.
        Vaccine. 2004; 22: 1343-1357
        • Marshall G.S.
        • Happe L.E.
        • Lunacsek O.E.
        • Szymanski M.D.
        • Woods C.R.
        • Zahn M.
        • et al.
        Use of combination vaccines is associated with improved coverage rates.
        Pediatr Infect Dis J. 2007; 26: 496-500
        • Shouval D.
        Hepatitis B vaccines.
        J Hepatol. 2003; 39: 70s-76s
        • Hollinger F.B.
        • Bell B.
        • Levy-Bruhl D.
        • Shouval D.
        • Wiersma S.
        • Van Damme P.
        Hepatitis A and B vaccination and public health.
        J Viral Hepat. 2007; 14: 1s-5s
        • Van Damme P.
        • Cramm M.
        • Safary A.
        • Vandepapeliere P.
        • Meheus A.
        Heat stability of a recombinant DNA hepatitis B vaccine.
        Vaccine. 1992; 10: 366-367
        • Hipgrave D.B.
        • Tran T.N.
        • Huong V.M.
        • Dat D.T.
        • Nga N.T.
        • Long H.T.
        • et al.
        Immunogenicity of a locally produced hepatitis B vaccine with the birth dose stored outside the cold chain in rural Vietnam.
        Am J Trop Med Hyg. 2006; 74: 255-260
        • Otto B.F.
        • Suarnawa I.M.
        • Stewart T.
        • Nelson C.
        • Ruff T.A.
        • Widjava A.
        At-birth immunization against hepatitis B using a novel pre-filled immunization device stored outside the cold chain.
        Vaccine. 1999; 18: 498-502
        • Odaka N.
        • Eldred L.
        • Cohn S.
        • Munoz A.
        • Fields H.A..
        • Fox R.
        • et al.
        Comparative immunogenicity of plasma and recombinant hepatitis B vaccines in homosexual men.
        JAMA. 1988; 260: 3635-3637
        • Francis D.P.
        • Hadler S.C.
        • Thompson S.E.
        • Maynard J.E.
        • Ostrow D.G.
        • Attman N.
        • 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
        • Coutinho K.A.
        • Lelie N.
        • Albrecht-Van Lent P.
        • Reerink-Brongers E.E.
        • Stoutjesdijk L.
        • Dees P.
        • et al.
        Efficacy of a heat inactivated hepatitis B vaccine in male homosexuals: outcome of a placebo-controlled double blind trial.
        Br Med J. 1983; 286: 1305-1308
        • Jefferson T.
        • Demicheli V.
        • Deeks J.
        • MacMillan A.
        • Sassi F.
        • Pratt M.
        Vaccines for preventing hepatitis B in health-care workers.
        Cochrane Database Syst Rev. 2000; (2): CD000100
        • Szmuness W.
        • Stevens C.E.
        • Harley E.J.
        • Zang E.A.
        • Alter H.J.
        • Taylor P.E.
        • et al.
        Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection.
        N Engl J Med. 1982; 307: 1481-1486
        • Crosnier J.
        • Jungers P.
        • Courouce A.M.
        • Laplanche A.
        • Benhamou E.
        • Degos F.
        • et al.
        Randomised placebo-controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units: I. Medical staff.
        Lancet. 1981; 1: 455-459
        • Desmyter J.
        • Colaert J.
        • De Groote G.
        • Reynders M.
        • Reerink-Brongers E.E.
        • Lelie P.N.
        • et al.
        Efficacy of heat-inactivated hepatitis B vaccine in haemodialysis patients and staff: double-blind placebo-controlled trial.
        Lancet. 1983; 2: 1323-1328
        • Crosnier J.
        • Jungers P.
        • Courouce A.M.
        • Laplanche A.
        • Benhamou E.
        • Degos F.
        • et al.
        Randomised placebo-controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units: II. Haemodialysis patients.
        Lancet. 1981; 1: 797-800
        • Centers for Disease Control and Prevention
        Recommendations for preventing transmission of infections among chronic dialysis patients.
        MMWR. 2001; 50: 1-43
        • Stevens C.E.
        • Alter H.J.
        • Taylor P.E.
        • Zang E.A.
        • Harley E.J.
        • Szmuness W.
        Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy.
        N Engl J Med. 1984; 311: 496-501
        • Schroth R.J.
        • Hitchon C.A.
        • Uhanova J.
        • Noreddin A.
        • Taback S.P.
        • Moffatt M.E.
        • et al.
        Hepatitis B vaccination for patients with chronic renal failure.
        Cochrane Database Syst Rev. 2004; (3): CD003775
        • Fraser G.M.
        • Ochana N.
        • Fenyves D.
        • Neumann L.
        • Chazan R.
        • Niv Y.
        • et al.
        Increasing serum creatinine and age reduce the response to hepatitis B vaccine in renal failure patients.
        J Hepatol. 1994; 21: 450-454
        • DaRoza G.
        • Loewen A.
        • Djurdjev O.
        • Love J.
        • Kempston C.
        • Burnett S.
        • et al.
        Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: earlier is better.
        Am J Kidney Dis. 2003; 42: 1184-1192
        • Kovacic V.
        • Sain M.
        • Vukman V.
        Efficient haemodialysis improves the response to hepatitis B virus vaccination.
        Intervirology. 2002; 45: 172-176
        • Ibrakim S.
        • el-Din S.
        • Bazzal I.
        Antibody level after hepatitis B vaccination in hemodialysis patients: impact of dialysis adequacy, chronic inflammation, local endemicity and nutritional status.
        J Natl Med Assoc. 2006; 98: 1953-1957
        • Navarro J.F.
        • Teruel J.L.
        • Mateos M.L.
        • Marcen R.
        • Ortuno J.
        Antibody level after hepatitis B vaccination in hemodialysis patients: influence of hepatitis C virus infection.
        Am J Nephrol. 1996; 16: 95-97
        • Benhamou E.
        • Courouce A.M.
        • Jungers P.
        • Laplanche A.
        • Degos F.
        • Brangier J.
        • et al.
        Hepatitis B vaccine: randomized trial of immunogenicity in hemodialysis patients.
        Clin Nephrol. 1984; 21: 143-147
        • Beleed K.
        • Wright M.
        • Eadington D.
        • Farr M.
        • Sellars L.
        Vaccination against hepatitis B infection in patients with end-stage renal disease.
        Postgrad Med J. 2002; 78: 538-540
        • Fabrizi F.
        • Andrulli S.
        • Bacchini G.
        • Corti M.
        • Locatelli F.
        Intradermal versus intramuscular hepatitis B re-vaccination in non-responsive chronic dialysis patients: a prospective randomized study with cost-effectiveness evaluation.
        Nephrol Dial Transplant. 1997; 12: 1204-1211
        • Micozkadioglu H.
        • Zumrutdal A.
        • Torun D.
        • Sezer S.
        • Ozdemir F.N.
        • Haberal M.
        Low-dose intradermal vaccination is superior to high-dose intramuscular vaccination for hepatitis B in unresponsive hemodialysis patients.
        Ren Fail. 2007; 29: 285-288
        • Mettang T.
        • Schenk U.
        • Thomas S.
        • Machleidt C.
        • Klefer T.
        • Fischer F.P.
        • et al.
        Low-dose intradermal versus intramuscular hepatitis B vaccination in patients with end-stage renal failure. A preliminary study.
        Nephron. 1996; 72: 192-196
        • Charest A.F.
        • McDougall J.
        • Goldstein M.B.
        A randomized comparison of intradermal and intramuscular vaccination against hepatitis B virus in incident hemodialysis patients.
        Am J Kidney Dis. 2000; 36: 976-982
        • Carne C.A.
        • Weller I.V.
        • Waite J.
        • Briggs M.
        • Pearce F.
        • Adler M.W.
        • et al.
        Impaired responsiveness of homosexual men with HIV antibodies to plasma-derived hepatitis B vaccines.
        Br Med J. 1987; 294: 866-868
        • Collier A.C.
        • Corey L.
        • Murphy V.L.
        • Handsfield H.H.
        Antibody to human immunodeficiency virus (HIV) and suboptimal response to hepatitis B vaccination.
        Ann Intern Med. 1988; 109: 101-105
        • Zuin G.
        • Principi N.
        • Tornaghi R.
        • Paccagnini S.
        • Re M.
        • Massironi E.
        • et al.
        Impaired response to hepatitis B vaccine in HIV infected children.
        Vaccine. 1992; 10: 857-860
        • Bruguera M.
        • Cremades M.
        • Salinas R.
        • Costa J.
        • Grau M.
        • Sans J.
        Impaired response to recombinant hepatitis B vaccine in HIV infected persons.
        J Clin Gastroenterol. 1992; 14: 27-30
        • Laurence J.C.
        Hepatitis A and B immunizations of individuals infected with human immunodeficiency virus.
        Am J Med. 2005; 118: 75s-83s
        • Paitoonpong L.
        • Suankratay C.
        Immunological response to hepatitis B vaccination in patients with AIDS and virologic response to highly active antiretroviral therapy.
        Scand J Infect Dis. 2008; 40: 54-58
        • Pippi F.
        • Bracciale L.
        • Stolzuoli L.
        • Giaccherini R.
        • Montomoli E.
        • Gentitle C.
        • et al.
        Serological response to hepatitis B virus vaccine in HIV-infected children in Tanzania.
        HIV Med. 2008; 9: 519-525
        • Degos F.
        • Duhamel G.
        • Brechot C.
        • Nalpas B.
        • Courouce A.M.
        • Tron F.
        • et al.
        Hepatitis B vaccination in chronic alcoholics.
        J Hepatol. 1986; 2: 402-409
        • Mendenhall C.
        • Roselle G.A.
        • Lybecker L.A.
        • Marshall L.E.
        • Grossman C.J.
        • Myre S.A.
        • et al.
        Hepatitis B vaccination: response of alcoholic with and without liver injury.
        Dig Dis Sci. 1988; 33: 263-269
        • Carey W.
        • Pimentel R.
        • Westveer M.K.
        • Vogt D.
        • Broughan T.
        Failure of hepatitis B immunization in liver transplant recipients: results of a prospective trial.
        Am J Gastroenterol. 1990; 85: 1590-1592
        • Loinaz C.
        • de Juanes J.R.
        • Gonzales E.M.
        • Lopez A.
        • Lumbreras C.
        • Gomez R.
        • et al.
        Hepatitis B vaccination results in 140 liver transplant recipients.
        Hepatogastroenterology. 1997; 44: 235-238
        • Arslan M.
        • Wiesner R.H.
        • Sievers C.
        • Egan K.
        • Zein N.N.
        Double-dose accelerated hepatitis B vaccine in patients with end-stage liver disease.
        Liver Transpl. 2001; 7: 314-320
        • Angelico M.
        • di Paolo D.
        • Trinito M.O.
        • Patrolati A.
        • Araco A.
        • Zazza S.
        • et al.
        Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis.
        Hepatology. 2002; 35: 176-181
        • Karasu Z.
        • Ozacar T.
        • Akarca U.
        • Ersoz G.
        • Erensoy S.
        • Gunsar F.
        • et al.
        HBV vaccination in liver transplant recipients: not an effective strategy in the prophylaxis of HBV recurrence.
        J Viral Hepat. 2005; 12: 212-215
        • Albeniz Arbizu E.
        • Barcena Marugan R.
        • Oton Nieto E.
        • Carrera Alonso E.
        • Garcia Gonzalez M.
        • Moreno Garica J.
        • et al.
        Prophylaxis of recurrent hepatitis B virus by vaccination after liver transplant: preliminary results.
        Transplant Proc. 2005; 35: 1848-1849
        • Lin C.C.
        • Chen C.L.
        • Concejero A.
        • Wang C.C.
        • Wang S.H.
        • Liu Y.W.
        • et al.
        Active immunization to prevent de novo hepatitis B virus infection in pediatric live donor liver transplant.
        Am J Transplant. 2007; 7: 195-200
        • Chen D.S.
        • Hsu N.H.M.
        • Sung J.L.
        • Hsu T.C.
        • Hsu S.T.
        • Kuo Y.T.
        • et al.
        A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
        JAMA. 1987; 257: 2597-2603
        • Feuerhake A.
        • Muller R.
        • Lauchart W.
        • Pichlmayr R.
        • Schmidt F.W.
        HBV vaccination in recipients of kidney allografts.
        Vaccine. 1984; 2: 255-256
        • Jacobson I.M.
        • Jaffers G.
        • Dienstag J.L.
        • Tolkoff-Rubin N.E.
        • Cosimi A.B.
        • Delmonico F.
        • et al.
        Immunogenicity of hepatitis B vaccine in renal transplant recipients.
        Transplantation. 1985; 39: 393-395
        • Choy B.Y.
        • Peiris J.S.
        • Chan T.M.
        • Lo S.K.
        • Lui S.L.
        • Lai K.N.
        Immunogenicity of intradermal hepatitis B vaccination in renal transplant recipients.
        Am J Transplant. 2002; 2: 965-969
        • Fabrizi F.
        • Martin P.
        • Dixit V.
        • Bunnapradist S.
        • Dulai G.
        Meta-analysis: the effect of age on immunological response to hepatitis B vaccine in end-stage renal disease.
        Aliment Pharmacol Ther. 2004; 20: 1053-1062
        • Lefebure A.F.
        • Verpooten G.A.
        • Couttenye M.M.
        • DeBroe M.E.
        Immunogenicity of a recombinant DNA hepatitis B vaccine in renal transplant patients.
        Vaccine. 1993; 11: 397-399
        • Horlander J.C.
        • Boyle N.
        • Manam R.
        • Schenk M.
        • Herring S.
        • Kwo P.Y.
        • et al.
        Vaccination against hepatitis B in patients with chronic liver disease awaiting liver transplantation.
        Am J Med Sci. 1999; 318: 304-307
        • Aziz A.
        • Aziz S.
        • Li D.S.
        • Murphy L.
        • Leone N.
        • Kennedy M.
        • et al.
        Efficacy of repeated high-dose hepatitis B vaccine (80 μg) in patients with chronic liver disease.
        J Viral Hepat. 2006; 13: 217-221
        • Bienzle U.
        • Günther M.
        • Neuhhaus R.
        • Vandepapeliere P.
        • Vollmar J.
        • Lun A.
        • et al.
        Immunization with an adjuvant hepatitis B vaccine after liver transplantation for hepatitis B-related disease.
        Hepatology. 2003; 38: 811-819
        • Rosenau J.
        • Hooman N.
        • Rifai K.
        • Solga T.
        • Tillmann H.L.
        • Grzegowski E.
        • et al.
        Hepatitis B virus immunization with an adjuvant containing vaccine after liver transplantation for hepatitis B-related disease: failure of humoral and cellular immune response.
        Transpl Int. 2006; 19: 828-833
        • Cruciani M.
        • Mengoli C.
        • Serpelloni G.
        • Mazzi R.
        • Bosco O.
        • Malena M.
        Granulocyte macrophage colony-stimulating factor as an adjuvant for hepatitis B vaccination: a meta-analysis.
        Vaccine. 2007; 25: 709-718
        • Rottinghaus S.T.
        • Poland G.A.
        • Jacobson R.M.
        • Barr L.J.
        • Roy M.J.
        Hepatitis B DNA vaccine induces protective antibody responses in human non-responders to conventional vaccination.
        Vaccine. 2003; 21: 4604-4608
        • Fazle Akbar S.M.
        • Furukawa S.
        • Yoshida O.
        • Hiasa Y.
        • Horiike N.
        • Onji M.
        Induction of anti-HBs in HB vaccine nonresponders in vivo by hepatitis B surface antigen-pulsed blood dendritic cells.
        J Hepatol. 2007; 47: 60-66
        • Payette P.J.
        • Ma X.
        • Weeratna R.D.
        • McCluski M.J.
        • Shapiro M.
        • Engle R.E.
        • et al.
        Testing of CpG-optimized protein and DNA vaccines against the hepatitis B virus in chimpanzees for immunogenicity and protection from challenge.
        Intervirology. 2006; 49: 144-151
        • Stevens C.E.
        • Taylor P.E.
        • Tong M.J.
        • Toy P.T.
        • Vyas G.N.
        • Nair P.V.
        • et al.
        Yeast-recombinant hepatitis B vaccine. Efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission.
        JAMA. 1987; 257: 2612-2616
        • Pongpipat D.
        • Suvatte V.
        • Assateerawatts A.
        Hepatitis B immunization in high risk neonates born from HBsAg positive mothers: comparison between plasma derived and recombinant DNA vaccine.
        Asian Pac J Allergy Immunol. 1989; 7: 37-40
        • Lee C.Y.
        • Huang L.M.
        • Chang M.H.
        The protective efficacy of recombinant hepatitis B vaccine in newborn infants of hepatitis B e antigen-positive hepatitis B surface antigen carrier mothers.
        Pediatr Infect Dis J. 1991; 10: 299-303
        • Poovorawan Y.
        • Sanpavat S.
        • Pongpunlert W.
        • Chumdermpadetsuk S.
        • Sentrakul P.
        • Vandepapelière P.
        • et al.
        Long-trem efficacy of hepatitis B vaccine in infants born to hepatitis B e antigen-positive mothers.
        Pediatr Infect Dis J. 1992; 11: 816-821
        • Stevens C.E.
        • Toy P.T.
        • Taylor P.E.
        • Lee T.
        • Yip H.Y.
        Prospects for control of hepatitis B virus infection: implications of childhood vaccination and long-term protection.
        Pediatrics. 1992; 90: 170-173
        • Assateerawatt A.
        • Tanphaichitr V.S.
        • Suvatte V.
        • Yodthong S.
        Immunogenicity and efficacy of a recombinant DNA hepatitis B vaccine, GenHevac B Pasteur in high risk neonates, school children and healthy adults.
        Asian Pac J Allergy Immunol. 1993; 11: 85-91
        • Poovorawan Y.
        • Sanpavat S.
        • Pongpunlert W.
        • Chumdermpadetsuk S.
        • Sentrakul P.
        • Safary A.
        Protective efficacy of a recombinant DNA hepatitis B vaccine in neonates of HBe antigen-positive mothers.
        JAMA. 1989; 261: 3278-3281
        • Milne A.
        • West D.J.
        • Chinh D.V.
        • Moyes C.D.
        • Poerschke G.
        Field evaluation of the efficacy and immunogenicity of recombinant hepatitis B vaccine without HBIG in newborn Vietnamese infants.
        J Med Virol. 2002; 67: 327-333
        • Lolekha S.
        • Warachit B.
        • Hirunyahote A.
        • Bowonkiratikachorn P.
        • West D.J.
        • Poerschke G.
        Protective efficacy of hepatitis B vaccine without HBIG in infants of HBeAg-positive carrier mothers in Thailand.
        Vaccine. 2002; 20: 3739-3743
        • Poovorawan Y.
        • Theamboonlers A.
        • Vimolket T.
        • Sinlaparatsamee S.
        • Chaiear H.
        • Siraprasiri T.
        • et al.
        Impact of hepatitis B immunisation as part of the EPI.
        Vaccine. 2001; 19: 943-949
        • Marion S.A.
        • Tomm Pastore M.
        • Pi D.W.
        • Mathias R.G.
        Long-term follow-up of hepatitis B vaccine in infants of carrier mothers.
        Am J Epidemiol. 1994; 140: 734-746
        • Ekra D.
        • Herbinger K.H.
        • Konates S.
        • Leblond A.
        • Fretz C.
        • Cilote V.
        • et al.
        A non-randomized vaccine effectiveness trial of accelerated infant hepatitis B immunization schedules with a first dose at birth or age 6 weeks in Côte d’Ivoire.
        Vaccine. 2008; 26: 2753-2761
        • Hipgrave D.B.
        • Maynard J.E.
        • Biggs B.A.
        Improving birth dose coverage of hepatitis B vaccine.
        Bull World Health Organ. 2006; 84: 65-71
        • Wang L.
        • Li J.
        • Chen H.
        • Li F.
        • Armstrong G.L.
        • Nelson C.
        • et al.
        Hepatitis B vaccination of newborn infants in rural China: evaluation of a village-based, out-of-cold-chain delivery strategy.
        Bull World Health Organ. 2007; 85: 688-694
        • Hsu H.M.
        • Chen D.S.
        • Chuang C.H.
        • Lu J.C.F.
        • Jwo D.M.
        • Lee C.C.
        • et al.
        Efficacy of a mass hepatitis B vaccination program in Taiwan.
        JAMA. 1988; 260: 2231-2235
        • Lee S.D.
        • Lo K.J.
        • Wu J.C.
        • Tsai Y.T.
        • Wang J.Y.
        • Ting L.P.
        • et al.
        Prevention of maternal-infant hepatitis B virus transmission by immunization: the role of serum hepatitis B virus DNA.
        Hepatology. 1986; 6: 369-373
        • Ip H.M.
        • Lelile P.N.
        • Wong V.C.
        • Kuhns M.C.
        • Reesink H.W.
        Prevention of hepatitis B virus carrier state in infants according to maternal serum levels of HBV DNA.
        Lancet. 1989; 1: 406-410
        • Söderström A.
        • Norkrans G.
        • Lindh M.
        Hepatitis B virus DNA during pregnancy and postpartum: aspects on vertical transmission.
        Scand J Infect Dis. 2003; 35: 814-819
        • Song Y.M.
        • Sung J.
        • Yang S.
        • Choe Y.H.
        • Chang Y.S.
        • Park W.S.
        Factors associated with immunoprophylaxis failure against vertical transmission of hepatitis B virus.
        Eur J Ped. 2007; 166: 813-818
        • Burk R.D.
        • Hwang L.Y.
        • Ho G.Y.
        • Shafritz D.A.
        • Beasley R.P.
        Outcome of perinatal hepatitis B virus exposure is dependent on maternal virus load.
        J Infect Dis. 1994; 170: 1418-1423
        • Volmink J.
        • Siegfried N.L.
        • van der Merwe L.
        • Brocklehurst P.
        Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection.
        Cochrane Database Syst Rev. 2007; (CD003510)
        • Van Zonneveld M.
        • van Nunen A.B.
        • Niesters H.G.
        • de Man R.A.
        • Schalm S.W.
        • Janssen H.L.
        Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection.
        J Viral Hepat. 2003; 10: 294-297
        • Lau Y.L.
        • Tam A.Y.
        • Ng K.W.
        • Tsoi N.S.
        • Lam B.
        • Lam P.
        • et al.
        Response of preterm infants to hepatitis B vaccine.
        J Pediatr. 1992; 121: 962-965
        • Freitas da Motta M.S.
        • Mussi-Pinhata M.M.
        • Jorge S.M.
        • Tachibana Y.C.F.
        • Sandoval de Souza C.B.
        Immunogenicity of hepatitis B vaccine in preterm and full-term infants vaccinated within the first week of life.
        Vaccine. 2002; 20: 1557-1562
        • Sood A.
        • Singh D.
        • Mehta S.
        • Midha V.
        • Kumar R.
        Response to hepatitis B vaccine in preterm babies.
        Indian J Gastroenterol. 2002; 21: 52-54
        • Patel D.M.
        • Butler J.
        • Feldman S.
        • Graves G.R.
        • Rhodes P.G.
        Immunogenicity of hepatitis B vaccine in healthy very low birth weight infants.
        J Pediatr. 1997; 131: 641-643
        • Saari T.N.
        • American Academy of Pediatrics Committee on Infectious Diseases
        Immunization of preferm and low birth weight infants.
        Pediatrics. 2003; 112: 193-198
        • Mahoney F.J.
        • Kane M.
        Hepatitis B vaccine.
        in: Plotkin S.A. Orenstein W.A. Vaccines. WB Saunders, Philadelphia1999: 158-182
        • West D.J.
        • Calandra G.B.
        Vaccine induced immunologic memory for hepatitis B surface antigen: implications for policy on booster vaccination.
        Vaccine. 1996; 14: 1019-1027
        • Lin C.Y.
        • Ni Y.H.
        • Chiang B.L.
        • Chen P.J.
        • Chang M.H.
        • Chang L.Y.
        • et al.
        Humoral and cellular immune responses to a hepatitis B vaccine booster 15–18 years after neonatal immunization.
        J Infect Dis. 2008; 197: 1419-1426
        • Chen D.S.
        Long-term protection of hepatitis B vaccine: lessons from Alaskan experience after 15 years.
        Ann Intern Med. 2005; 142: 384-385
        • Edmunds W.J.
        • Medley G.F.
        • Nokes D.J.
        • Hall A.J.
        • Whittle H.C.
        The influence of age on the development of the hepatitis B carrier state.
        Proc Roy Soc B Biol Sci. 1993; 253: 197-201
        • Lin Y.C.
        • Chang M.H.
        • Ni Y.H.
        • Hsu H.Y.
        • Chen D.S.
        Long-term immunogenicity and efficacy of universal hepatitis B virus vaccination in Taiwan.
        J Infect Dis. 2003; 187: 134-138
        • Boxall E.H.
        • Sira J.A.
        • El-Shuhkri N.
        • Kelly D.A.
        Long-term persistence of immunity to hepatitis B after vaccination during infancy in a country where endemicity is low.
        J Infect Dis. 2004; 190: 1264-1269
        • Yuen M.F.
        • Lim W.L.
        • Chan A.O.O.
        • Wong D.K.H.
        • Sum S.S.M.
        • Lai C.L.
        18-year follow-up study of a prospective randomized trial of hepatitis B vaccinations without booster doses in children.
        Clin Gastroenterol Hepatol. 2004; 2: 941-945
        • McMahon B.J.
        • Bruden D.L.
        • Peterson K.M.
        • Bulkow L.R.
        • Parkinson A.J.
        • Nainan O.
        • et al.
        Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up.
        Ann Intern Med. 2005; 142: 333-341
        • Dentiger C.M.
        • McMahon B.J.
        • Butler J.C.
        • Dunaway C.E.
        • Zanis C.L.
        • Bulkow L.R.
        • et al.
        Persistence of antibody to hepatitis B and protection from disease among Alaskan natives immunized at birth.
        Pediatr Infect Dis J. 2005; 24: 786-792
        • Zanetti A.R.
        • Mariano A.
        • Romanò L.
        • D’Amelio R.
        • Chironna M.
        • Coppola R.C.
        • et al.
        Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study.
        Lancet. 2005; 366: 1379-1384
        • Alter M.J.
        • Hadler S.C.
        • Margolis H.S.
        • Alexander W.J.
        • Hu P.Y.
        • Judson F.N.
        • et al.
        The changing epidemiology of hepatitis B in the United States. Need for alternative vaccination strategies.
        JAMA. 1990; 263: 1218-1222
        • Arevalo J.A.
        • Washington A.E.
        Cost-effectiveness of prenatal screening and immunization for hepatitis B virus.
        JAMA. 1988; 259: 365-369
        • Van Damme D.
        • Kane M.
        • Meheus A.
        Integration of hepatitis B vaccination into national immunisation programmes.
        Br Med J. 1997; 314: 1033-1036
        • Anonymous
        Hepatitis B vaccine in the expanded programme of immunisation: the Gambian experience.
        Lancet. 1989; 1: 1057-1059
        • Ruff R.A.
        • Gertig D.M.
        • Otto B.F.
        • Gust I.D.
        • Sutano A.
        • Soewarso T.I.
        • et al.
        Lombok hepatitis B model immunization project: towards universal hepatitis B immunization in Indonesia.
        J Infect Dis. 1995; 171: 290-296
        • Chen D.S.
        Hepatitis B virus infection, its sequelae, and prevention in Taiwan.
        in: Okuda K. Ishak K.G. Neoplasms of the liver. Springer-Verlag, Tokyo1987: 69-80
        • Hsu H.M.
        • Lu C.F.
        • Lee S.C.
        • Lin S.R.
        • Chen D.S.
        Seroepidemiologic survey for hepatitis B virus infection in Taiwan: the effect of hepatitis B mass immunization.
        J Infect Dis. 1999; 179: 367-370
        • Chang M.H.
        Hepatitis B virus infection.
        Semin Fetal Neonatal Med. 2007; 12: 160-167
        • Kao J.H.
        • Hsu H.M.
        • Shau W.Y.
        • Chang M.H.
        • Chen D.S.
        Universal hepatitis B vaccination and the decreased mortality from fulminant hepatitis in infants in Taiwan.
        J Pediatr. 2001; 139: 349-352
        • Chen H.L.
        • Chang C.J.
        • Kong M.S.
        • Huang F.C.
        • Lee H.C.
        • Lin C.C.
        • et al.
        Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination.
        Hepatology. 2004; 39: 58-63
        • Mele A.
        • Tosti M.E.
        • Mariano A.
        • Pizzuti R.
        • Ferro A.
        • Borrini B.
        • et al.
        Acute hepatitis B 14 years after the implementation of universal vaccination in Italy: areas of improvement and emerging challenges.
        Clin Infect Dis. 2008; 46: 868-875
        • Mele A.
        • Mariano A.
        • Tosti M.E.
        • Stroffolini T.
        • Pizzuti R.
        • Gallo G.
        • et al.
        Acute hepatitis delta virus infection in Italy: incidence and risk factors after the introduction of universal anti-hepatitis B vaccination campaign.
        Clin Infect Dis. 2007; 44: e17-e24
        • Goh K.T.
        Prevention and control of hepatitis B virus infection in Singapore.
        Ann Acad Med Singapore. 1997; 26: 671-681
        • Bhimma R.
        • Coovadia H.M.
        • Adhikari M.
        • Connolly C.A.
        The impact of hepatitis B virus vaccine on the incidence of hepatitis B virus-associated membranous nephropathy.
        Arch Pediatr Adolesc Med. 2003; 157: 1025-1030
        • Xu H.
        • Sun L.
        • Zhou L.J.
        • Sheng F.Y.
        • Guo Y.Q.
        The effect of hepatitis B vaccination on the incidence of childhood HBV-associated nephritis.
        Pediatr Nephrol. 2003; 18: 1216-1219
        • Chang M.H.
        • Chen D.S.
        • Hsu H.C.
        • Hsu H.Y.
        • Lee C.Y.
        Maternal transmission of hepatitis B virus in childhood hepatocellular carcinoma.
        Cancer. 1989; 64: 2377-2380
        • Chang M.H.
        • Chen C.J.
        • Lai M.S.
        • Hsu H.M.
        • Wu T.C.
        • Kong M.S.
        • et al.
        Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children.
        N Engl J Med. 1997; 336: 1855-1859
        • Lee C.L.
        • Ko Y.C.
        Hepatitis B vaccination and hepatocellular carcinoma in Taiwan.
        Pediatrics. 1997; 99: 351-353
        • Lee C.L.
        • Hsieh K.S.
        • Ko Y.C.
        Trends in the incidence of hepatocellular carcinoma in boys and girls in Taiwan after large-scale hepatitis B vaccination.
        Cancer Epidemiol Biomarkers Prev. 2003; 12: 57-59
        • Chang M.H.
        • Chen T.H.
        • Hsu H.M.
        • Wu T.C.
        • Kong M.S.
        • Liang D.C.
        • et al.
        Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems.
        Clin Cancer Res. 2005; 11: 7953-7957
        • Lee M.S.
        • Kim D.H.
        • Kim H.
        • Lee H.S.
        • Kim C.Y.
        • Park T.S.
        • et al.
        Hepatitis B vaccination and reduced risk of primary liver cancer among male adults: a cohort study in Korea.
        Int J Epidemiol. 1998; 27: 316-319
        • Li R.C.
        • Yang J.Y.
        • Gong J.
        • Li Y.P.
        • Huang Z.N.
        • Fang K.X.
        • et al.
        Efficacy of hepatitis B vaccination on hepatitis B prevention and on hepatocellular carcinoma.
        Zhonghua Liu Xing Bing Xue Za Zhi (Chin J Epidemiol). 2004; 25: 385-387
        • Madani T.A.
        Trend in incidence of hepatitis B virus infection during a decade of universal childhood hepatitis B vaccination in Saudi Arabia.
        Trans Roy Soc Trop Med Hyg. 2007; 101: 278-283
        • Bohlke K.
        • Davis R.L.
        • Marcy S.M.
        • Braun M.M.
        • DeStefano F.
        • Black S.B.
        • et al.
        Risk of anaphylaxis after vaccination of children and adolescents.
        Pediatrics. 2003; 112: 815-820
        • Duclos P.
        Safety of immunization and adverse events following vaccination against hepatitis B.
        J Hepatol. 2003; 39: 83s-88s
        • Carman W.F.
        • Zanetti A.R.
        • Karayiannis P.
        • Waters J.
        • Manzillo G.
        • Tanzi E.
        • et al.
        Vaccine-induced escape mutant of hepatitis B virus.
        Lancet. 1990; 336: 325-329
        • Hsu H.Y.
        • Chang M.H.
        • Ni Y.H.
        • Chen H.L.
        Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination program in Taiwan.
        Gut. 2004; 53: 1499-1503
        • Kalinia T.
        • Iwanski A.
        • Will H.
        • Sterneck M.
        Deficiency in virion secretion and decreased stability of the hepatitis B immune escape mutant G145R.
        Hepatology. 2003; 38: 1274-1281
        • Mele A.
        • Tancredi F.
        • Romano L.
        • Giuseppone A.
        • Coluci M.
        • Sangiulo A.
        • et al.
        Effectiveness of hepatitis B vaccination in babies born to hepatitis B surface antigen-positive mothers in Italy.
        J Infect Dis. 2001; 184: 905-908
        • Ogata N.
        • Cote P.J.
        • Zanetti A.R.
        • Miller R.H.
        • Shapiro M.
        • Gerin J.
        • et al.
        Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus.
        Hepatology. 1999; 30: 779-786
        • Namgyal P.
        Impact of hepatitis B immunization, Europe and worldwide.
        J Hepatol. 2003; 39: 77s-82s
        • Zuckerman J.
        • Van Hattum J.
        • Cafferkey M.
        • Gjorup I.
        • Hoel T.
        • Rummukainen M.L.
        • et al.
        Should hepatitis B vaccination be introduced into childhood immunization programmes in northern Europe?.
        Lancet Infect Dis. 2007; 7: 410-419
        • Pollard A.J.
        Hepatitis B vaccination. The BMA adds its voice to the call for universal childhood immunisation in the UK.
        Br Med J. 2007; 335: 950
        • Anonymous
        Hepatitis B as of July 2006, Japan.
        Infect Agents Surveill Rep. 2006; 27: 217-218
        • Kao J.H.
        • Chen D.S.
        Universal hepatitis B vaccination: killing two birds with one stone.
        Am J Med. 2008; 121: 1029-1031