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Department of Medicine, Division of Nephrology
A. Fleming General Hospital. Athens, Greece




Hepatitis B (HB), through chronicity leading to cirrhosis and liver carcinoma even after renal transplantation, contributes to morbidity and mortality in haemodialysis patients. Hepatitis B vaccination protects against HB virus infection.

Suppressed immunity in renal failure results to low HB vaccination success rates. Uremia, inadequate dialysis, use of low biocompatibility dialysis material, hyperparathyroidism, anemia, iron overload and malnutrition contribute to depressed immunity. Chronic inflammation associated with renal failure, leads to impaired monokine production and decreased immunity. This impairment could be related to defective HLA-DRB7 02 expression on monocytes. Non-responders to Hepatitis B vaccination express increased levels of HLA class II alleles (T-cell immune response modulators) DRB1 01 (DR1) and DRB1 15 (DR15).

Various methods (recombinant adjuvants, thymopentine, IL-2, levamisole and GM-CSF) have been used to enhance immune response to HB vaccination with conflicting results. Better dialysis biocompatibility and adequacy have also been proposed to overcome this low immune response to HB vaccination, which is considered an index of inadequate dialysis and inflammatory state, both associated with unfavorable cardiovascular outcome and survival. Recombinant erythropoietin treatment of anemia contributes to reestablish immunity.

HB vaccination reinforcement techniques evolved from an initial intramuscular double/multiple-dosing regimen to more frequent intradermal smaller dose injections. This newer regimen achieves a higher and almost complete seroconversion rate, although frequent boosters shots are necessary to maintain protective levels. Experience with pre-S1/S2, third generation, vaccines is limited and they have not been proven to be more effective than intradermally administered second generation S antigens.


Chronic renal failure, quite early in its course, exhibits specific and non-specific humoral and mainly cellular immune deficiency. Cellular immune deficiency, worsening with dialysis, is based on reduced T cell activation of the accessory antigen presenting cells (APC) in most patients [1-2]. Most immunocompetant cells show a paradoxical coexistence of a functional deficiency, together with phenotypic signs of T cell activation [2]. Monocytes and the co-stimulatory system of the B7/CD28 pathway are involved (table 1) [3-6].

Table 1: Immune deficiency in uremia-mechanism

Monocyte activation is a part of the uremic syndrome even before End Stage Renal Disease (ESRD) and dialysis have been reached. When patients start dialysis, complement activation by membrane material or endotoxin contaminated solutions lead to additional monocyte activation. Monokines, like IL-1, IL-6 and TNF-α, activated by the retention of renal metabolites in uremia and by chronic inflammation (induced by dialysis material), are systematically released in patients on renal failure or haemodialysis (table 1). This cytokine activation can also be seen in various clinical consequences of renal failure and dialysis, besides immune dysfunction, such as amyloidosis, malnutrition, atherosclerosis and anemia [3, 5, 7-8].

High production of proinflammatory cytokines is thus associated with a heavily impaired immune system. This overproduction is, at least partially, genetically defined (by gene polymorphism) thus explaining the variable presence of the inflammatory state in renal failure patients [7-8]. Genetically defined inability to produce the necessary IL-10 (a cytokine feedback mechanism resulting in better B cell function) in order to control the overproduction of proinflammatory monokines (IL-6, TNF-α) both in renal failure and in end stage renal disease is linked to the immune defect [2]. Patients producing higher levels of IL-10 exhibit reduced uremia and dialysis induced chronic inflammation and respond better to vaccines (table 1) [3, 7-8].

Various genetic mechanisms have been cited to explain the defective immune response in haemodialysis patients. Genetic markers have been extensively studied in the group of no responders to hepatitis B vaccine, as unresponsiveness to this vaccine is quite common among ESRD patients. Major Histocompatibility Complex (MHC) genes have been found to control the response to vaccinations. In various studies, non-response to HB recombinant vaccine was shown to be related, at least in Caucasian populations, to HLA DR3 and/or DR7 alleles, especially when they were found to be present on extended haplotypes: HLA B8-SC01-DR3 and HLA B44- FC31-DR7. Other studies have found that non-response to HB vaccination is related to the presence of HLA A2, DRB1 0101 or A1, B8, DR3, DR7, DR14 and DQ2 and to the absence of HLA B18, B51, DRB1 0301 and DR15. These differences perhaps can be explained due to small sample sets, ethnicity background differences or to serologic typing methods (table 2) [1, 5, 9-15].

Table 2: Factors depressing immunity in uremia
Uremic syndrome (inflammation, anemia, malnutrition, hyperparathyroidism)
Age (old)
Sex (female)
Body weight (overweight)
Iron overload
Genetics (MHC: HLA DR3/DR7 presence, B18, 51-DRB1 0101-DR15 absence)
Dialysis (method, efficacy, biocompatibility)

These genetic findings could be explained by the presence of a dominant immune gene in MHC, responsible for normal response (helper T cells activation) and, when present in MHC extended haplotypes on both chromosomes, responsible for low or no response (suppressor T cells activation) to HB virus (HBV) (or vaccine antigens) [12].

HLA DR3 was found associated with high TNF-α production, suggesting that this histocompatibility marker may play a role in regulating immune suppressive genes controlling the response to HB (S) antigen. However, more vigorous stimulation produces anti-HB (S) antibodies arguing in favor of a multifactor origin of the genetic immune defect (table 2) [5].

Specific antibody production, after hepatitis B vaccination, is generated via B-cell activation by class II (CD4+ Th1-helper) and class I restricted T-cell (CD8+ CTL-cytotoxic T cells) responses. Insufficient B and T-cell responses lead to chronic liver disease in 5-15% of the general population and in 30% of HBV infected dialysis patients [2, 16].

Immune suppression is associated with uremia and dialysis (toxins, low biocompatibility dialysis material, anemia, iron overload, trace element depletion, vitamin deficiency, malnutrition, secondary hyperparathyroidism) and leads to high susceptibility to infections, life-threatening sepsis and reduced response to vaccination [2, 17-20]. The number of blood transfusions and the presence of a hepatitis C virus (HCV) infection or diabetes mellitus are considered additional factors for the decreased immune response [21-23]. Indeed, response to hepatitis B vaccination is reported to be very low, in patients with hepatitis C virus infection, which suggests a possible genetic basis for low responder status to both viruses (table 2) [5, 22-23].

Scanty information exists concerning the relationship between dialysis adequacy, immune function and antibody response to vaccinations. There is, however, indirect evidence that more frequent dialysis may lead to an enhanced response because dialysis helps to restore impaired B7-2 expression [4]. In a study of peritoneal dialysis patients immunized with the hepatitis B vaccine, the initial weekly Kt/V was 2.37 and 2.01 in responders and non-responders respectively, although other investigators could not confirm such a favorable action of dialysis on immune function [5, 14, 19].

As a result of depressed immunity, dialysis patients are not able to respond to HB vaccination and when they do respond they develop lower antibody titers and do not maintain adequate antibody levels over time, compared to a healthy population [5, 24-27]. Some authors suggest that antibody response to HB vaccination can be correlated to the degree of renal failure but not to the specific dialysis mode (peritoneal dialysis or haemodialysis) while others suggest that antibody response can be modulated by the type of dialysis used [20, 24].

Intradermal route of HB vaccination provides a stronger cellular and humoral stimulus than intramuscular injections, purportedly by recruiting relatively immature dermal dendritic Langerhans cells, which serve as antigen presenting cells [16].

There is less information concerning the response of ESRD and dialysis patients to tetanus, pneumococcus, diphtheria, influenza, varicella-zoster virus, and staphylococcus aureus vaccines [24-25, 28-32].

The antibody response to these vaccines in renal failure patients is also reported to be less than optimal [20, 32]. A prospective controlled study evaluating the response to tetanus and hepatitis B vaccines among patients with chronic renal failure, dialysis patients, transplant recipients, and healthy controls, found that antibody titers were lower in the groups with renal failure than in healthy vaccinated controls. Patients, who had previously responded to hepatitis B vaccine, were more likely to respond to tetanus vaccine, implying that a subset of patients have an intact immune system [25]. In other studies, however, tetanus and diphtheria vaccination responses have been found to be independent of responses to hepatitis B vaccination. This difference could be explained by the use of various vaccine preparation methods or by the presence of preexisting undetected antibodies to tetanus and diphtheria [24, 28].

The immune response in patients with ESRD is generally defective whenever T cell activation is required (hepatitis B, tetanus, influenza vaccine), while it is found almost normal when non-T dependent immunity mechanisms are activated (pneumococcal vaccine) [25]. Despite the evidence for decreased efficacy, current recommendations are to vaccinate patients with ESRD [20, 32].

Recipients of renal transplants respond to vaccines in a manner similar to chronic dialysis patients, as a result of immunosuppressive treatments such as cyclosporine administration. The antibody response is often less in these patients than in healthy controls and protective titers fall rapidly. Thus administration of vaccine is recommended, in susceptible patients, prior to transplantation. Post transplant vaccination or booster shots, have been safely applied in these patients [10, 17, 20, 25-26, 30-31, 33]. Live attenuated vaccines (Measles, Mumps, Rubella, Varicella) should be avoided in transplanted patients [20, 31].


Hepatitis B infection in dialysis centers depends on the disease’s prevalence in general and particularly in the dialysis population. Hepatitis B has been on the decline in the last decade in renal units, a consequence of efficient prophylaxis measures. The most important factor in preventing the spread of hepatitis B in haemodialysis units has been the maintenance of universal precautions. CDC recommends isolating antigen-positive patients, treatment by a separate nursing team and prohibiting the use of shared medications (e.g., common heparin vials) in dialysis units [34-35]. High rates of exposure to hepatitis B virus were noticed only in renal units treating HB (S) Ag carriers. This exposure can be successfully limited by the above strict isolation procedures but despite this, accidents can spread the infection to the entire unit [1, 21, 34-37].

Hepatitis B vaccination in renal patients initially by a plasma derived vaccine containing attenuated live virus, although first reported 21 years ago as creating sufficient protection, has not been universally accepted as an efficient prophylaxis measure. Acceptance is limited mainly because of the unstable results in producing adequate response in all patients [10, 34, 36-42].

HB vaccination, when applied together with the other preventive measures, resulted in an up to 10fold drop in the number of new HB cases in haemodialysis patients and renal unit staff in Western Europe and in the United States [21, 34, 37, 43-44].

Although the incidence of the disease is actually very low, a high percentage of susceptible patients are still not vaccinated. Rules for the limitation of transmissible diseases in renal units give a sense of security to the staff, however, patient vaccination is still considered a secondary and costly procedure leading to a high percentage of unvaccinated patients. In USRDS report only 18.3% of adult patients were vaccinated against HBV in 2000. CDC suggests that the cost of vaccinating patients is mitigated by the reduced need for monthly surveillance of antigen and antibody status in those who develop specific antibodies [21, 34, 36-37, 39, 43, 45].

Hepatitis B is still a threat for dialysis patients, despite prophylactic measures, not only when they undergo dialysis in their home unit, but also when, with better patient rehabilitation, holiday traveling and dialysis in host centers is made possible. In these scenarios, the susceptible patient serves both as a potential HBV infection target (dialyzed in HBV positive centers) and as a transmitter of the disease back to the home unit [21, 35-36, 42, 46-47]. HBV could also infect dialysis patients by means common in the general population (sex etc). Infected patients can then spread the disease in their unit, before HB infection has been detected, if patients are not actively protected by a successful vaccination program [36].

A high percentage of dialysis patients becoming HBV positive will be unable to eliminate their virus (developing chronic hepatic disease). They are considered high risks for renal transplantation and are virus reservoirs to both other patients and non-protected staff [37]. A completely successful vaccination program is essential for patient and personnel protection against this chronic, persistent and potentially lethal disease [1, 21, 27, 34, 36, 40, 42, 44, 48].


Controversy exists concerning the overall effectiveness, including the cost/benefit ratio, of hepatitis B vaccination in patients with ESRD [10, 12, 14, 20, 22-23, 26-27, 34-43, 45, 47, 49-55].

Second generation recombinant vaccines (expressing the ‘S’ gene), have replaced plasma-derived vaccines (table 3). These vaccines are safer and result in immunogenicity levels similar to those seen in control patients [1, 45, 51].

Table 3: HBV Vaccinations
1st Generation 1980 Plasma derived vaccines
2nd Generation 1988 Recombinant vaccines (pre-S: Engerix-Recombivax)
3rd Generation 2001 Recombinant vaccines (pre-S-S1-S2: Hepacare)

Third generation recombinant vaccines containing pre-S1, pre-S2 and S antigenic components of both viral surface antigen subtypes adw and ayw, are currently under investigation in healthy and renal failure non responder patients: results to date are mixed [6, 56]. Pre-S components have been found to be more immunogenic than simple S containing vaccines by some authors, as they could overcome genetically defined unresponsiveness and protect even against emerging HBV mutants (G145R vaccine related mutations in 5% of vaccinated infants) resistant to anti-S antibodies [56].

Multiple attempts have been made to enhance the low immune response rate to the hepatitis B vaccine among patients with ESRD.

These attempts include recommendations as in table 4 [1, 5-6, 9-10, 14, 17, 20-21, 23, 26-27, 35, 37, 40-43, 47, 49-50, 54, 57-63].

Table 4: HBV Vaccination Protocols in uremia
Single dose (20μg) (3 doses)
Double dose (40μg) (3 doses)
(IL-2, IFN-α, G-M CSF, thymopentine, levamisole)


5-10 μg per 7-15 days (4-8 doses)

Intramuscular booster dose:

20-40μg in 6-12 months
additional if fall of antibody titer 10 mIU/ml

According to some authors, general measures associated with the elimination of "uremic" factors mentioned above, should be taken, in order to decrease the effect on immune defenses: erythropoietin and vitamin administration, hyperparathyroidism and iron overload treatment, use of more biocompatible dialysis material, efficient dialysis and better nutrition [17-19, 21, 58, 64]. Other investigators question the efficacy of such measures [27].

Incomplete protection and response variability are reported in chronic renal failure and haemodialysis patients, vaccinated against Hepatitis B by the classical intramuscular route [1, 22-23, 27, 40-41, 43, 47, 49, 57, 65-67].

In contrast to intramuscular administration, intradermal administration (the vaccine antigen remains trapped for long periods in the dermis, leading to longer macrophage dependent T cell stimulation and consequent higher immune response, with the aid of specific cells-relatively immature dendritic Langerhans cells) of small multiple doses, tried first in healthy and later in uremic non-responder patients, has proved to be simple, safe and relatively non-expensive method of HB vaccination, with, sometimes absolute, success in producing protective and lasting antibody titers in dialysis patients [1, 11, 21, 40, 43, 46, 48-49, 52, 57-58, 65, 68]. This method enables costs to be reduced enough to become manageable for dialysis patients [21, 40, 43, 46, 49, 52, 53, 58, 65, 68-70]. In our studies, protective levels were achieved even in patients not responsive to multiple-double quantity intramuscular doses. These findings have been confirmed by others [21, 52, 57, 65, 68, 70].

The degree of renal failure was not found to correlate to the attained level of immune response. Haemodialysis patients and renal failure patients not yet on dialysis reacted similarly to the injected antigen and produced similar levels of antibody "Fig. (1), (2)" [68].

Figure 1

Figure 2

In contrast others have reported that as with IM administration, efficacy is lower in haemodialysis patients, even after vaccination with twice the number of doses used by our group. These differences may be explained by variations in application, population age, time in dialysis and dialysis adequacy [19, 21, 43, 48-49, 52]. Mettang et al and others also point out the importance of a strict intradermal vaccination technique (table 5) [21, 40, 49, 58].

Table 5: Differences in HBV Vaccination Protocols in uremia
 Intradermal (vs. Intramuscular)
Less vaccine (economy)

Difficult technique

More doses

100% response

Earlier response

Lower peak antibody levels

Need for more frequent boosters?

Our studies did not show factors associated with low or no response to the vaccine such as age, sex, body weight, degree of renal failure, time on haemodialysis, secondary hyperparathyroidism, HCV carrier state, dialysis modalities, serum albumin, hematocrit and hemoglobin levels, number of transfusions and erythropoietin treatment [5, 13, 18, 22-23, 27, 45, 47, 49, 54, 66]. Other authors insist on the importance of these factors as well as of the dialysis modality on the immune response (CAPD patients showing better response rates compared to haemodialysis patients) [1, 12, 19-23, 27, 50, 58, 71]. Our patients, vaccinated by the ID protocol, gradually lose adequate protection, after the first year, in contrast to those receiving IM vaccination (table 5).

Both routes were equally efficient in the first 12 months of observation "Fig. (3)" [11, 13, 21, 27, 40, 43, 52-53, 57-58]. Shorter follow up, longer initial vaccination times, alone or combined with higher total vaccine doses, besides the different approach to the booster method (IM or ID), could explain these differences [21, 40, 43, 52-53, 57-58].

Figure 3
Comparison of the immune response to HBV vaccine (Intradermal vs. Intramuscular) during 48 months

Peak antibody titers after ID vaccination are weaker than those achieved by intramuscular administration (table 5) [21, 40, 48, 53, 58, 65, 68, 70].

Although the ID method produces a universal and quick initial seroconversion and higher seroprotection rate in haemodialysis patients, compared to the IM route, seroprotection disappears quicker compared to the IM vaccination [40, 43, 53]. This is the reason why an increased need for boosters with ID method is noted (table 5) [57-58].

Despite seroprotection loss, patients can remain adequately protected, as long as frequent (yearly) titer measurements are taken, proving the long-term efficiency of the method. Consequently, timing for additional booster has to be closely followed-up when ID vaccination is applied [40, 53, 57].

Intramuscular vaccination against HBV together with ID administration of the vaccine to non responders to IM vaccination, using small total antigenic loads and limited numbers of inoculations, together with frequent, yearly, antibody level measurements and booster administration whenever protective levels were not detected, succeeded in preventing the appearance of new HB cases in our unit [21, 26, 68, 70]. Thus, vaccination against hepatitis B with recombinant (S) vaccine, first with the IM method and then, in non responders to IM, with the ID method, protects immunocompromised end stage renal disease patients as efficiently as it does in the healthy population [1, 12, 21, 26, 43, 57-58].


Renal failure patients with low producing IL-10 genotypes, which show no-response to hepatitis B vaccines may harbor an immune defect that is genetically defined. T cell CD4+ dysfunction and abnormal antigen presenting cells are the main causes of this immune defect.

This low or no response to HB vaccine can serve as an index of immune suppression in dialysis in patients and poor dialysis adequacy. Accordingly depressed immunity is also considered an additional, together with inadequate dialysis, inflammation and resulting malnutrition, risk factor for atherosclerosis, poor cardiovascular outcome and survival in ESRD.

Anemia correction by r-erythropoietin associated to lymphocyte subsets changes (increase in T helper/suppressor ratio) as well as better dialysis biocompatibility both contribute to better immune response to vaccination.

Both Intramuscular and Intradermal vaccination against hepatitis B have been used with variable efficiency in haemodialysis. The combination of IM and ID (for non responders) vaccination protocols succeeded, in some studies, in protecting up to 100% of the renal failure population.

Intradermal antigen presentation lasts longer, possible because it mobilizes dendritic Langerhans cells, leading to a more sustained stimulus that overcomes the "uremic" immune defect.

Immune response strength to Hepatitis B vaccine in haemodialysis patients is equivalent when immunization is conducted via either the IM or ID methods. However, later, antibody titers are found significantly lower in the ID immunization group. Consequently, these patients need more frequent, yearly, serum HBV(S)Ab measurements and booster doses when titers are found unprotective.

Multiple intradermal vaccination against HB virus, using a smaller total vaccine dose, is a safe, quick, cost/effective and successful approach that can be used in all susceptible predialysis and dialysis patients. The disadvantage to this method is that specific antibody titers decrease over time, thus necessitating the administration of additional boosters.

Second generation recombinant HB vaccines, intradermally administered, can overcome the immune defect in all renal failure patients. This ID vaccination protocol can successfully be used to vaccinate non-responder renal failure or ESRD patients until other methods have been proven effective. Third generation recombinant HB vaccines with S, pre-S1 and immunodominant domain pre-S2 genes have been shown to have promise and may eventually replace ID vaccination. Alternatively adjuvants for strong and specific stimulation of the immune response may provide enhanced vaccination efficacy.

Lecture based on the review: Recombinant Hepatitis B Vaccination in Renal Failure. Patients by D. Vlassopoulos in: Curr Pharm Biotechnology, 4(2): 141-151, 2003.


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HB=Hepatitis B
HBV= Hepatitis B virus
HB (S) Ag=Hepatitis B surface antigen
CRF=Chronic Renal Failure
ESRD= end stage renal disease
CAPD=Continuous Ambulatory Peritoneal Dialysis
TNF=Tumor Necrosis Factor
G-M CSF= Granulocyte-Macrophage Colony Stimulating Factor
Kt/V=dialysis adequacy index
CDC=Center for Disease Control
APC=Antigen Presenting Cell
MHC= Major Histocompatibility Complex
TCR=T Cell Receptor
ICAM=Intracellular Adhesion Molecule
HLA=Histocompatibility Locus A
Th=T helper
HCV= Hepatitis C Virus
CTL=Cytotoxic T Lymphocytes