Journal of Hepatology
Volume 43, Issue 2 , Pages 203-206, August 2005

The questionable role of immunization against hepatitis B in HBV infected liver transplant patients

  • Didier Samuel

      Affiliations

    • Centre HépatoBiliaire, EA 3541, Faculté de Médecine Paris Sud, Hôpital Paul Brousse Assistance Publique-Hôpitaux de Paris, 12 Avenue Paul Vaillant-Couturier, 94800 Villejuif, France
    • Corresponding Author InformationCorresponding author. Tel.: +33 1 45 59 34 03; fax: +33 1 45 59 38 57.
    • ,
  • Daniel Shouval

      Affiliations

    • Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel

published online 13 June 2005.

See Article, pages 283--287

Article Outline

 

Over the past 10 years, results of liver transplantation for hepatitis B virus infection have dramatically improved. The advent of long-term passive immune prophylaxis with high dose anti-HBs immune globulins (HBIG) and of nucleos(t)ide analogues has led to a dramatic decrease of HBV re-infection rate, and has been associated with significant improvement in patient's survival [1], [2]. More recently the use of combination prophylaxis with HBIG plus lamivudine or adefovir after transplantation has proven to be extremely effective against HBV graft recurrence by reducing the rate of HBV re-infection to less than 10% even in patients who were HBV DNA positive pre-transplantation [3], [4], [5], [6]. However, although these prophylactic regimens are highly effective, attempts continue to develop new, less costly means to protect patients at risk against HBV re-infection Each type of prophylaxis has its own drawbacks. Several limitations of HBIG prophylactic treatment have been identified: First, HBIG therapy post-transplantation, may fail to prevent HBV re-infection in those patients who were highly viremic pre-transplantation; second, the high cost of long-term HBIG administration; third, HBV re-infection may occur despite the umbrella of circulating HBIG due to emergence of HBV escape mutants with mutations in the preS/S region of the HBV genome. These drawbacks of long-term HBIG administration and the introduction of lamivudine, a potent nucleoside analogue against HBV with an overall good tolerance, prompted some centres to use lamivudine monoprophylaxis post-transplant instead of long-term administration of HBIG. The first results with lamivudine monoprophylaxis post-transplantation were encouraging with an HBV recurrence rate around 10% after 1 year [7]. However, long-term follow-up showed a much higher recurrence rate between 35 and 50% after 4 years following viral breakthrough due to the mutation in the YMDD part of the polymerase gene of HBV [8], [9]. No data has been provided on adefovir monoprophylaxis post-transplant. In patients receiving lamivudine monoprophylaxis, the intermediate post-transplant virologic profile is completely distinct from that of patients receiving HBIG alone or in combination with nucleoside analogue. Indeed, in patients receiving HBIG, HBsAg becomes undetectable in the majority of patients during the first days after transplantation in association with a high serum anti-HBS level. In contrast, in patients receiving lamivudine, HBsAg remains positive, progressively declining over a period of several months during the first post-transplant period to become undetectable without anti-HBs production [7]. In a recent original paper, Lo et al. [10] described the appearance of serum anti-HBs antibody after transplantation in 21 out of 50 chronic Chinese HBV carriers receiving lamivudine monoprophylaxis after transplantation. The authors suggested that this increase of anti-HBs antibody level was most probably the consequence of active anti-HBs production by engrafted lymphocytes. Anti-HBs antibody production in recipients started about 8 days after liver transplantation with a peak serum level at 3 months, which supports the hypothesis of an active production of anti-HBs by the HBV immune donor lymphocytes, transferred during the transplantation process. It is well known that donor lymphocytes may be transferred with the solid liver graft. Anti-HBs antibodies were already detected within 8 days post-transplantation, and continued to rise thereafter in some patients. However, it was not clear if anti-HBs was secreted by circulating or engrafted donor lymphocytes and whether the latter would respond to an HBsAg challenge with a secondary rise in anti-HBs antibody titers. Furthermore, in two recipients, the production of anti-HBs antibodies from non-anti-HBs positive donors remained unexplained in this study. Nevertheless, the original report by Lo et al. confirmed some anecdotal reports that humoral immunity against HBsAg may also be transferred (although transiently) and sometimes with residual virus through solid organ-liver transplantation [11]. Indeed, adoptive transfer of immunity to HBV envelope and nucleocapside epitopes of HBV was already demonstrated in the early and mid 1990s in patients receiving bone marrow (BMT) or peripheral stem cell transplantation from HBV immune donors [12], [13], [14], [15]. This transfer of immune memory was also demonstrated in experimental models in mice receiving BMT [16], in rats transplanted with livers and bone marrow from HBV immunized donors [17], in woodchucks with or without persistent woodchuck hepatitis virus infection [18] and in rats receiving kidney transplantation from immunized donors [19]. Lo et al. provided the first evidence in a relatively large cohort of patients that this phenomenon of adoptive immune transfer may also be active in patients transplanted with livers from HBV immune donors (regardless if this donor immunity was obtained through ‘natural infection’ or through active immunization against HBV) [10], [20].

They also hypothesized that the production of anti-HBS was facilitated by downregulation of HBV replication by lamivudine. However, the protective effect of this transferred anti-HBs production was probably insufficient to prevent HBV recurrence. Indeed, serum levels of anti-HBs have been declining over time, and only 4 out of the 10 patients with adoptive immune transfer and a 1 year follow-up have had anti-HBs level over 12mIU/ml. In this issue of the Journal, Lo et al. [21] report their attempt to vaccinate these patients, while continuing lamivudine monoprophylaxis. Success of adoptive transfer of immunity to HBV envelope protein(s) using the above technique requires proof that transplanted patients acquire immune memory against HBV which will respond to booster vaccination with a secondary anamnestic rise in anti-HBs levels. In this report, Lo et al. have vaccinated their patients using three double doses of a commercially available recombinant hepatitis B vaccine (40μg/injection) administered by the intramuscular route into the deltoid muscle at month 0, 1 and 2 (at a median interval of 412 days post-transplant). Response was defined by anti-HBS antibody titre over 10mIU/ml. Early non-responders, together with the early responders whose anti-HBs response was not sustained at month 6 of the study received a second course of vaccination consisting of an additional three intramuscular doses, given at month 6, 7, and 8 after enrolment. After the first course of vaccination, only two patients (3.8%) had a low titre of anti-HBs of 12mIU/ml. However, this response was not sustained and anti-HBs level dropped below 10mIU/ml at month 3. One of these patients developed an antibody response of 27mIU/ml at month 6 after the second vaccination cycle. Two other patients developed a first response to the second course of vaccination of 17 and 103mIU/ml at month 9 after the entry into the study. The overall response rate was low at 7.7% and only 1 out of 52 (1.9%) patients developed antibody response over 100mIU/ml. The results of this study are clearly disappointing for several reasons. If HBV immune lymphocytes transferred through solid organ transplantation were indeed engrafted in the recipient, we might have expected a much better response rate to booster vaccination. It is now clear from these results that this anti-HBs antibody production observed initially by Lo et al. in their previous paper was most probably not due to the active production of anti-HBs antibody by engrafted donor lymphocytes. It seems that this adoptive transfer of immunity to HBsAg was transient and disappeared with the clearance of cells of donor origin in the recipient. Alternatively, this underlines the fact that the phenomenon of adoptive transfer of immunity under the conditions tested was insufficient, weak and transient following liver transplantation. In this context, it is important to compare the results of Lo and co-workers with the results of BMT recipients transplanted with bone-marrow or peripheral immune lymphocytes from anti-HBs positive donors in humans as well as in mice and rats [12], [13], [16], [17]. In humans undergoing such manoeuvres, active transfer of immune memory was documented repeatedly through generation of a secondary anamnestic response to booster vaccination, which was not demonstrated in the study by Lo et al. [21], [22], [23]. The question remains open whether this difference in results may be explained by the transfer of a relatively too low number of immune lymphocytes via solid organ transplantation which are insufficient to provide the basis for clonal expansion of stimulated B cells with an adequate immune memory. Support for such an hypothesis can be derived from the study of Li et al. [17] who performed simultaneous transplantation of bone marrow and liver from HBsAg immunized rats and were able to demonstrate a secondary booster effect on the immune memory.

The results of the rather low response rate to the HBV booster vaccination in the study of Lo and co-workers should be compared to previous attempts at HBV vaccination after liver transplantation in HBsAg positive patients. Although it may appear as bizarre to try to vaccinate against HBV patients chronically infected with HBV, HBV vaccines have been used with low to moderate success in HBV chronic carriers in an attempt to clear HBV infection in liver transplant recipients at risk, with or without an umbrella of HBIG. Such a strategy has been tried, although with very limited success also in patients with persistent HBV infection using what is termed ‘vaccinotherapy’ [24], [25]. Theoretically, removal of the HBV infected liver at transplantation with continuous HBIG and or nucleoside analogue therapy, eliminating the main reservoir of virus, should provide optimal conditions for introduction of a vaccine. Indeed, active vaccination against HBV after transplantation has already been attempted with discordant results in patients transplanted for HBV infection [26], [27]. In the study from Barcelona, HBV vaccination was performed using a commercially available vaccine in 18 patients at 18 months post-transplantation. Initial seroconversion revealed a 62% response rate. However, longer follow-up provided evidence that, anti-HBs titres were declining over time, and the final results were not so optimistic. In Rome, the group of Angelico et al. used a fortified vaccine protocol with poor results since only 17% of patients developed an antibody response >10mIU/ml following post-transplant immunization [27]. In these last two studies, the prophylaxis protocol against HBV re-infection using long-term administration of HBIG, was discontinued before the start vaccination. Evidently the currently licensed vaccines seem to be inadequate in inducing a long-lasting protective humoral and cellular immune response in immune suppressed individuals after liver transplantation. However, there still is hope that this resistance may be over come and there are currently a number of experimental approaches to by-pass this non-responsiveness. One interesting approach is the substitution of the traditionally used alum-hydroxide adjuvant present in all licensed HBV vaccines with more potent adjuvants such as MPL&QS21 [28]. In a recent study conducted by the Berlin group, this newly formulated vaccine was given to HBV transplant patients under an umbrella of HBIG with gradual withdrawal of the polyclonal immune globulin, once rising anti-HBs titers were documented. A remarkable anti-HBs response was documented in ∼80% of patients rising >1000mIU/ml. These excellent results, which demonstrate bypass of tolerance or immune suppression by a very immunogenic HBV vaccine require further confirmation and so far a similar study in Hannover was less conclusive [29].

Thus where are we with protection of HBV patients undergoing liver transplantation against re-infection? Previous observations confirm that some patients transplanted for end-stage HBV infection may spontaneously develop an anti-HBs response, which may be masked by the continuous administration of HBIG. This may have particular relevance for patients who have undergone liver transplantation for fulminant HBV infection and developed spontaneous seroconversion at the date of transplantation with resolution of HBV altogether which remains unrecognized under HBIG therapy We have also previously shown that ∼50% of patients receiving HBIG have at 10 years post-transplantation still low levels of HBV DNA in the liver or in PBMCs despite being HBsAg negative [6]. The question remains open what are the reasons why some patients may respond to active vaccination while others do not. Will it be possible to ‘educate’ the immune system of liver transplant recipients to develop an adequate anti-HBV response using adoptive transfer of immunity and/or a more immunogenic vaccine with a better adjuvant or with Pre-S/S antigens.

We know that before the advent of HBIG immune prophylaxis, HBV re-infection was not always the rule and that 20% of the patients did not get re-infected. This phenomenon was more frequent in patients transplanted for fulminant hepatitis B and HDV cirrhosis. It is therefore possible that HBV vaccine stimulate antibody response in those patients who have already cleared HBV. This hypothesis requires proof through randomized study. In addition to the selection of patients for HBV vaccination, the question of the impact of additional prophylactic treatment has been raised. In the Berlin study, the authors claimed that the good antibody response was due also to the fact that patients received at the same time HBV vaccine and HBIG in contrast to other studies were HBV vaccine was given after HBIG discontinuation. This latter hypothesis requires further confirmation. In the study by Lo et al., an HBV vaccine was given in patients who did not received HBIG and the results are poor. Will it be possible to improve the results by adding to the protocol post-transplantation immunization against HBV using a more immunogenic vaccine containing either S or Pre-S antigens without or with core epitopes? As a first step, we should be able to identify those patients who are able to develop an anti-HBs response particularly among those who are under an umbrella of HBIG. If a strong antibody response occurs, HBV prophylaxis may be no longer required. Finally, the aim of these strategies is to provide definite protection against HBV re-infection. We should, however, provide proof that this antibody response is neutralizing and effective and long-lasting before conventional prophylaxis against HBV reinfection either by HBIG or by lamivudine/adefovir can be discontinued.

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PII: S0168-8278(05)00372-7

doi:10.1016/j.jhep.2005.05.017

Journal of Hepatology
Volume 43, Issue 2 , Pages 203-206, August 2005

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