In recent years, orthotopic liver transplantation (OLT) has become the treatment of choice for patients with end-stage liver disease. The improvement in survival rates in transplant patients has been attributed to a number of factors, including better surgical techniques, new and more conservative use of immunosuppressive agents, and improved diagnostic methods for identifying and preventing infections. Despite these advances, infection problems still represent a major cause of morbidity and mortality after OLT. Among transplant recipients, hepatitis virus infections represent one of the major problems. De novo hepatitis B infection after OLT has been reported in 1–3.5% of patients [1–3]. Potential sources of infection include transfusion of blood products, reactivation of latent infection in the recipient, and grafting of organs from donors who are negative for hepatitis B surface antigen (HBsAg) and positive for antibody to hepatitis core antigen (HBcAb). In the latter case, the risk of developing de novo hepatitis B infection varies from 16 to 50%[2–4]. Based on this high transmission rate, many authors have considered patients with HBcAb as unsuitable liver donors who should therefore be excluded. The application of such a policy in areas with a high prevalence of HBcAb in the general population would represent the loss of an unacceptably high number of livers given the shortage of organ donors. On the other hand, the achievement of protective titres of anti-HBs through vaccination has been suggested to be protective in this setting . In order to avoid the acquisition of de novo hepatitis B infection, patients who are waiting for OLT are systematically vaccinated against hepatitis B virus (HBV).
First-generation hepatitis B vaccines use the hepatitis B surface antigen, present as a surplus non-infectious protein coat of HBV, purified from the plasma of asymptomatic human carriers and subsequently subjected to at least two inactivation procedures. Second-generation vaccines based on recombinant DNA hepatitis B surface antigen protein have replaced plasma-derived vaccines in most countries. Although currently available hepatitis B vaccines are extremely safe and have an efficacy of more than 90% in the general population, the response rate is slightly lower in obese individuals, smokers and men, and significantly lower in patients with cirrhosis or chronic renal failure, organ transplant recipients and immunosuppressed patients. In cirrhotic patients, due to the impairment in T-cell-dependent function, the results of vaccination in transplant candidates have been very disappointing, with response rates to recombinant HBV vaccine of 20–30%[5–9]. Several factors have been correlated with these low protection rates, including age > 40 years, male sex, high body mass index, site of injection, HLA haplotype, and stage and aetiology of liver disease [6,10–12]. Moreover, in responder patients, immunosuppressive treatments frequently lead to a decrease in serum antibody titres after transplantation.
Initial schedules using 20 μg of recombinant hepatitis B surface antigen, given at 0, 1 and 6 months, showed a very low response rate (15–20%) [5,6]. In addition, the time required for completion of a course of vaccination usually exceeded the interval from listing to transplantation. Due to this low efficacy, attempts to induce complete immunization with accelerated protocols, using either 20 or 40 μg, have given discordant results. Kallinowski et al., using an accelerated vaccination protocol (0, 7 and 21 days) with 20 μg of recombinant surface antigen, found that only 7 of 20 (36%) liver transplant candidates developed anti-HBs titres above 10 mU/ml. More recently, based on encouraging results obtained among alcoholics and patients with chronic renal failure entering dialysis [13,14], high-dose/short-term schedules have been tried in cirrhotic patients awaiting OLT. Domínguez et al., using an accelerated protocol (0, 1 and 2 months) with 40 μg of recombinant HBsAg in 62 patients with end-stage liver disease awaiting OLT, showed protective antibody responses in 44%. Furthermore, revaccination of initial non-responders increased the overall response rate to 62%, suggesting that revaccination of non-responders would be an even better strategy in this setting.
In the present issue, Engler et al. compare two accelerated schedules of recombinant hepatitis B vaccine in 34 patients awaiting OLT. All patients were vaccinated with an accelerated schedule (0, 7 and 21 days) using either 20 μg (14 patients) or 40 μg (20 patients) of hepatitis B surface antigen. Both schedules were well tolerated, and, 8 weeks after the third injection, no differences were observed in seroprotective rates between the groups (31 and 26%, respectively). Based on the poor response to vaccination even with high-dose/short-term schedules and the low risk of acquiring de novo hepatitis B infection after OLT, the authors, as suggested by other groups, questioned whether routine HBV vaccination prior to OLT should still be recommended.
De novo hepatitis B infection after OLT is a rare event, with an incidence of 1–3% of cases, and usually runs a mild clinical and histological course with little morbidity, as opposed to that in patients with chronic hepatitis B suffering allograft re-infection after transplantation. Despite the favourable outcome of these patients, a wide spectrum of HBV-associated liver disease may develop, ranging from asymptomatic carriage to severe chronic active hepatitis or cirrhosis and even fulminant hepatic failure . Due to this potential morbidity and mortality, the low cost and the excellent safety profile of the vaccine, it seems reasonable that most centres continue to recommend routine HBV vaccination of all cirrhotic patients waiting for liver transplantation.
Alternative strategies to further increase the response rate in cirrhotic patients have been proposed. Intradermal inoculation has been suggested to induce a better immune response than the intramuscular route despite being more cumbersome [18–20]. In haemodialysed patients, who show, like cirrhotic patients, a low response to HBV vaccination, response rates have been shown to increase from 50 to up to 70% using intradermal vaccination schedules .
Some authors have proposed that the concomitant administration of certain immunomodulators, such as interleukin-2 or interferon α or γ, along with conventional HBV vaccine, increases the response in patients undergoing haemodialysis . Again, however, studies using this approach have obtained discordant results . Also, several immune adjuvants are being investigated for their ability to enhance the antigen-specific immune response to hepatitis B vaccine antigen. Among them, non-aluminium-based monophosphoryl lipid A (MPL) and MF-59 [23,24] seem to be the most promising. These new adjuvants act by increasing the production of selected immunoglobulin sub-classes, by enhancing MHC-I- and II-restricted immune responses and T-helper reactivity (both Th1 and Th2) . Preliminary studies suggest that these new adjuvants, especially MPL, can induce higher titres of anti-HBs with very good tolerance, but further studies (some currently ongoing) are needed to confirm these results.
Results with experimental animals suggest that the use of DNA-based vaccines or so-called genetic vaccination (vaccines that contain plasmid vectors encoding specific antigens) may induce protective immunity in animal models , but data from human trials are not yet available.
Preliminary clinical studies involving a large group of non-responders to the standard vaccine have shown that revaccination with a pre-S1/pre-S2-containing vaccine induced higher response rates than revaccination with the conventional (S-containing) vaccine . These encouraging results remain to be confirmed.
Finally, as the low antibody response to vaccination in cirrhotics is the result of the impairment of the immune response associated with end-stage liver disease, it is of primary importance that these patients be vaccinated at an earlier stage of their liver disease. Universal vaccination of all newborns should eventually lead to eradication of HBV infection.
In summary, despite the low efficacy of various vaccination schedules reported by most authors in cirrhotic patients awaiting OLT, the use of more immunogenic formulations (containing new adjuvants or additional pre-S1/pre-S2 recombinant antigens) and, more importantly, early vaccination of potential transplant candidates at earlier stages of their liver disease should further prevent de novo hepatitis B in transplant recipients and allow safe allocation of HBcAb-positive grafts in responding recipients. Further studies are warranted to establish the best immunization schedule.
1. Fabia R, Levy M, Crippin J, Tillery W, Netto G, Aguanno J. et al
. De novo
hepatitis B infection after liver transplantation: sources of disease, incidence and impact. Liver Transpl Surg 1998; 4: 119 –127.
2. Dickson RC, Everhart JE, Lake JR, Wei Y, Seaberg E, Wiesner R. et al
. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Gastroenterology 1997; 113: 1668 –1674.
3. Dodson SF, Issa S, Araya V, Gayawsky T, Pinna A, Eghtesad B. et al
. Infectivity of hepatic allografts with antibodies to hepatitis B virus. Transplantation 1997; 64: 1582 –1584.
4. Castells Ll, Vargas V, Rodriguez-Frias F, Allende H, Jardí R, Margarit C. et al
. Transmission of hepatitis B virus infection by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Transpl Proc 1999; 31: 2464 –2465.
5. Van Thiel DH, el-Ashmawy L, Love K, Gavaler JS, Starzl TE. Response to hepatitis B vaccination by liver transplant candidates. Dig Dis Sci 1992; 37: 1245 –1249.
6. Chalasani N, Smallwood G, Halcomb J, Fried MW, Boyer TD. Is vaccination against hepatitis B infection indicated in patients waiting for or after orthotopic liver transplantation? Liver Transpl Surg 1998; 4: 128 –132.
7. Kallinowski B, Benz C, Buchholz L, Stremmel W. Accelerated schedule of hepatitis B vaccination in liver transplant candidates. Transpl Proc 1998; 30: 797 –799.
8. Horlander JC, Boyle N, Manam R, Schenk M, Herring S, Kwo PY. et al
. Vaccination against hepatitis B in patients with chronic liver disease awaiting liver transplantation. Am J Med Sci 1999; 318: 304 –307.
9. Villeneuve E, Vincelette J, Villeneuve JP. Ineffectiveness of hepatitis B vaccination in cirrhotic patients waiting for liver transplantation. Can J Gastroenterol 2000; 14 (suppl) : 59B –62B.
10. Lemon S, Thomas DL. Vaccines to prevent viral hepatitis. N Engl J Med 1997; 336: 196 –214.
11. Nowicki MJ, Tong MJ, Bohman RE. Alterations in the immune response of nonresponders to hepatitis B vaccine. J Infect Dis 1985; 152: 1245 –1248.
12. Shaw FE, Guess HA, Roets JM, Mohr FE, Coleman PJ, Mandel EJ. et al
. Effect of anatomic injection site, age and smoking on the immune response to hepatitis B vaccination. Vaccine 1989; 7: 425 –430.
13. Seaworth B, Drucker J, Starling J, Drucker R, Stevens C, Hamilton J. Hepatitis B vaccines in patients with chronic renal failure before dialysis. J Infect Dis 1988; 157: 332 –337.
14. Rosman AS, Basu P, Galvin K, Lieber CS. Efficacy of a high and accelerated dose of hepatitis B vaccine in alcoholic patients. A randomized clinical trial. Am J Med 1997; 103: 217 –222.
15. Domínguez M, Bárcena R, García M, López-Sanroman A, Nuño J. Vaccination against hepatitis B virus in cirrhotic patients on liver transplantation waiting list. Liver Transpl 2000; 6: 440 –442.
16. Engler SH, Sauer PW, Golling M, Klar EA, Benz C, Stremmel W, Kallinowski B. Immunogenicity of two accelerated hepatitis B vaccination protocols in liver transplant candidates. Eur J Gastroenterol Hepatol 2001; 13: 363 –367.
17. Crespo J, Fábrega E, Casafont F, Rivero M, De las Heras G, Peña J. et al
. Severe clinical course of de novo
hepatitis B infection after liver transplantation. Liver Transpl Surg 1999; 5: 175 –183.
18. Propst T, Propst A, Lhotta K, Vogel W, Koning P. Reinforced intradermal hepatitis B vaccination in hemodialysis patients is superior in antibody response to intramuscular or subcutaneous vaccination. Am J Kidney Dis 1998; 32: 1041 –1045.
19. Rahman F, Dahmen A, Herzog-Hauff S, Bocher WO, Galle PR, Lohr HF. et al
. Cellular and humoral immune responses induced by intradermal or intramuscular vaccination with the major hepatitis B surface antigen. Hepatology 2000; 31: 521 –527.
20. Rault R, Freed B, Nespor S, Bender F. Efficacy of different hepatitis B vaccination strategies in patients receiving hemodialysis. ASAIO J 1995; 41: 717 –719.
21. Quiroga JA, Carreño V. Interferon and hepatitis B vaccine in haemodialysis patients. Lancet 1989; i: 1264. 1264.
22. Jungers P, Devillier P, Salomon H, Cerisier JE, Courouce AM. Randomised placebo-controlled trial of recombinant interleukin-2 in chronic ureamic patients who are non-responders to hepatitis B vaccine. Lancet 1994; 344: 856 –857.
23. Thoelen S, Van Damme P, Mathei C, Leroux-Roels G, Desombere I, Safary A. et al
. Safety and immunogenicity of hepatitis B vaccine formulated with a novel adjuvant system. Vaccine 1998; 16: 708 –714.
24. Traquina P, Morandi M, Contorni M, Van Nest G. MF-59 adjuvant enhances the antibody response to recombinant hepatitis B surface antigen vaccine in primates. J Infect Dis 1996; 174: 1168 –1175.
25. Gupta RK, Siber GR. Adjuvants for human vaccines – current status, problems and future prospects. Vaccine 1995; 13: 1263 –1276.
26. Milich DR, Thorton GB, Neurath AR, Kent SB, Michel ML, Tiollais P. et al
. Enhanced immunogenicity of the pre-S region of hepatitis B surface antigen. Science 1985; 228: 1195 –1199.
27. Zuckerman JN, Sabin C, Craig FM, Williams A, Zuckerman AJ. Immune response to a new hepatitis B vaccine in healthcare workers who had not responded to standard vaccine: randomised double blind dose–response study. BMJ 1997; 314: 329 –333.