Hepatitis B vaccination: The key towards elimination and eradication of hepatitis B
Authors: Ding-Shinn Chen
Journal: Journal of Hepatology (2009)

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. 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. 1. IntroductionHepatitis 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) [[1]Chen D.S. From hepatitis to hepatoma: lessons from type B viral hepatitis.Science. 1993; 262: 369-370Crossref PubMed Google Scholar]. Worldwide, as many as 360 million people are chronically infected with HBV, and ∼1 million deaths are attributed to its infection [[2]Margolis H.S. Fact sheets for candidate diseases for elimination or eradication. Hepatitis B virus infection.Bull World Health Organ. 1998; 76: 152-153PubMed Google Scholar]. 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 [[3]Kao J.H. Chen D.S. Global control of hepatitis B virus infection.Lancet Infect Dis. 2002; 2: 395-403Abstract Full Text Full Text PDF PubMed Scopus (541) Google Scholar].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 [[4]Fenner F. Candidate viral diseases for elimination or eradication.Bull World Health Organ. 1998; 76: 68-70PubMed Google Scholar]. 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 [[5]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: 1056-1075Crossref PubMed Scopus (417) Google Scholar]. On the other hand, from the very beginning, the hepatitis B vaccine has proved to prevent HBV infection effectively [6Szmuness 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: 833-841Crossref PubMed Google Scholar, 7Maupas 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: 289-292Abstract PubMed Scopus (103) Google Scholar]. Vaccination of infants against hepatitis B, especially those born to HBV carrier mothers [[8]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: 1099-1102Abstract PubMed Scopus (448) Google Scholar] 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 vaccineIn 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 [[9]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: 868-871Crossref PubMed Scopus (2987) Google Scholar]. 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 [[10]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: 1287-1293Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar], 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 [11Shapira 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: 123-127Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 12Young 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: 372-376Crossref PubMed Scopus (42) Google Scholar]. Additionally, improvement of the adjuvants to make the vaccine more immunogenic has also been tried [[13]Kundi M. New hepatitis B vaccine formulated with an improved adjuvant system.Expert Rev Vaccines. 2007; 6: 133-140Crossref PubMed Scopus (89) Google Scholar].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 [14Pichichero 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: 43-49Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 15Ortega-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: 8432-8440Crossref PubMed Scopus (9) Google Scholar] and hexavalent [[16]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: 1343-1357Crossref PubMed Scopus (27) Google Scholar] 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 [[17]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: 496-500Crossref PubMed Scopus (49) Google Scholar]. The development of hepatitis B vaccines and the public health strategy of hepatitis B vaccination have been reviewed recently [18Shouval D. Hepatitis B vaccines.J Hepatol. 2003; 39: 70s-76sAbstract Full Text Full Text PDF PubMed Google Scholar, 19Hollinger 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-5sCrossref PubMed Scopus (13) Google Scholar].The vaccine should be kept at 2–8 °C and should never be frozen. It is relatively heat-stable [[20]Van Damme P. Cramm M. Safary A. Vandepapeliere P. Meheus A. Heat stability of a recombinant DNA hepatitis B vaccine.Vaccine. 1992; 10: 366-367Crossref PubMed Google Scholar], the immunogenicity does not change when the vaccine is stored for up to one month at ambient temperature [[21]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: 255-260PubMed Google Scholar] or even at tropical temperature [[22]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: 498-502Crossref PubMed Scopus (29) Google Scholar]. The heat stability helps greatly to deliver the vaccine in places where refrigeration is not available.3. Effectiveness of vaccinationHepatitis 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 settingsThe 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 [6Szmuness 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: 833-841Crossref PubMed Google Scholar, 23Odaka 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: 3635-3637Crossref PubMed Google Scholar, 24Francis 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: 362-366Crossref PubMed Google Scholar, 25Coutinho 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: 1305-1308Crossref PubMed Google Scholar]. In health-care workers, hepatitis B vaccine appears to be efficacious [[26]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): CD000100Google Scholar], especially in high-risk health-care workers, such as staff of renal hemodialysis units [27Szmuness 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: 1481-1486Crossref PubMed Google Scholar, 28Crosnier 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: 455-459Abstract PubMed Scopus (81) Google Scholar, 29Desmyter 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: 1323-1328Abstract PubMed Scopus (59) Google Scholar]. Patients with end-stage renal disease (ESRD) on hemodialysis are also protected by the vaccine [29Desmyter 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: 1323-1328Abstract PubMed Scopus (59) Google Scholar, 30Crosnier 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: 797-800Abstract PubMed Scopus (124) Google Scholar, 31Centers for Disease Control and Prevention Recommendations for preventing transmission of infections among chronic dialysis patients.MMWR. 2001; 50: 1-43PubMed Google Scholar], however, not all studies demonstrated that ESRD patients receiving hemodialysis benefit from hepatitis B vaccination [32Stevens 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: 496-501Crossref PubMed Google Scholar, 33Schroth 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): CD003775PubMed Google Scholar]. 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%) [[34]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: 450-454Abstract Full Text PDF PubMed Scopus (29) Google Scholar]. Those with glomerular filtration rate <10 mL/min, >60 years of age, and diabetes mellitus are less likely to seroconvert after immunization [[35]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: 1184-1192Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar]. Efficient hemodialysis improves the response to hepatitis B vaccine [36Kovacic V. Sain M. Vukman V. Efficient haemodialysis improves the response to hepatitis B virus vaccination.Intervirology. 2002; 45: 172-176Crossref PubMed Scopus (21) Google Scholar, 37Ibrakim 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: 1953-1957PubMed Google Scholar]. A coexisting hepatitis C virus infection may reduce the effectiveness of the vaccine in patients on maintenance hemodialysis [[38]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: 95-97Crossref PubMed Google Scholar]. The poor response to hepatitis B vaccine can be rescued with reinforced vaccination protocols by increasing the dose or number of the vaccines [39Benhamou 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: 143-147PubMed Google Scholar, 40Beleed 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: 538-540Crossref PubMed Scopus (31) Google Scholar]. Changing the route of vaccine administration from intramuscular to intradermal injections has also been claimed to improve the immunogenicity and may be cost-effective [41Fabrizi 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: 1204-1211Crossref PubMed Scopus (81) Google Scholar, 42Micozkadioglu 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: 285-288Crossref PubMed Scopus (21) Google Scholar]. 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 [43Mettang 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: 192-196Crossref PubMed Google Scholar, 44Charest 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: 976-982Abstract Full Text Full Text PDF PubMed Google Scholar]. 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 [45Carne 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: 866-868Crossref PubMed Google Scholar, 46Collier 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: 101-105Crossref PubMed Google Scholar, 47Zuin 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: 857-860Crossref PubMed Scopus (42) Google Scholar, 48Bruguera 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: 27-30Crossref PubMed Google Scholar]. 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 [[49]Laurence J.C. Hepatitis A and B immunizations of individuals infected with human immunodeficiency virus.Am J Med. 2005; 118: 75s-83sAbstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. 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 [[49]Laurence J.C. Hepatitis A and B immunizations of individuals infected with human immunodeficiency virus.Am J Med. 2005; 118: 75s-83sAbstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. 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 [49Laurence J.C. Hepatitis A and B immunizations of individuals infected with human immunodeficiency virus.Am J Med. 2005; 118: 75s-83sAbstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 50Paitoonpong 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: 54-58Crossref PubMed Scopus (22) Google Scholar] and children [[51]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: 519-525Crossref PubMed Scopus (18) Google Scholar].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 [52Degos F. Duhamel G. Brechot C. Nalpas B. Courouce A.M. Tron F. et al.Hepatitis B vaccination in chronic alcoholics.J Hepatol. 1986; 2: 402-409Abstract Full Text PDF PubMed Google Scholar, 53Mendenhall 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: 263-269Crossref PubMed Google Scholar]. In patients with non-hepatitis B chronic liver disease who receive liver transplant, the anti-HBs seroconversion rate is low after hepatitis B vaccination [54Carey 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: 1590-1592PubMed Google Scholar, 55Loinaz 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: 235-238PubMed Google Scholar, 56Arslan 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: 314-320Crossref PubMed Scopus (56) Google Scholar]. The responses in those transplanted for HBV-related cirrhosis are especially poor, even after a reinforced triple course of vaccination [[57]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: 176-181Crossref PubMed Scopus (153) Google Scholar] or a double course of recombinant vaccine containing pre-S1, pre-S2 and S protein [[58]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: 212-215Crossref PubMed Scopus (25) Google Scholar], 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) [[59]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: 1848-1849Abstract Full Text Full Text PDF Scopus (24) Google Scholar]. Protection was especially evident in Taiwanese pediatric patients in a recent study [[60]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: 195-200Crossref PubMed Scopus (35) Google Scholar]. In the study, all the 60 patients had received hepatitis B vaccination previously in a national infant hepatitis B vaccination program [[61]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: 2597-2603Crossref PubMed Google Scholar]. 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 [62Feuerhake A. Muller R. Lauchart W. Pichlmayr R. Schmidt F.W. HBV vaccination in recipients of kidney allografts.Vaccine. 1984; 2: 255-256Crossref PubMed Google Scholar, 63Jacobson 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: 393-395Crossref PubMed Google Scholar]. Increased dose and intradermal route of vaccination have also been tried to improve the immunogenicity with some success [[64]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: 965-969Crossref PubMed Scopus (26) Google Scholar]. Because age of the patient has been shown to correlate with immune response to hepatitis B vaccine in patients with ESRD [[65]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: 1053-1062Crossref PubMed Scopus (53) Google Scholar], and the immunogenicity is much higher if the vaccine is given before renal transplantation [[66]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: 397-399Crossref PubMed Scopus (37) Google Scholar], 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 [39Benhamou 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: 143-147PubMed Google Scholar, 40Beleed 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: 538-540Crossref PubMed Scopus (31) Google Scholar, 67Horlander 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: 304-307Crossref PubMed Google Scholar, 68Aziz A. Aziz S. Li D.S. Murphy L. Leone N. Kennedy M. et al.Efficacy of repeated high-dose h