Solid organ transplantation and response to vaccination

Vaccine 25 (2007) 7331–7338

Solid organ transplantation and response to vaccination Beatriz Serrano a,∗ , Jose-Mar´ıa Bayas a , Laia Bruni b , Consolaci´on D´ıez a a

Preventive Medicine Service, Adult Vaccination Centre, Hospital Clinic-IDIBAPS, Villarroel 170, 08036 Barcelona, Spain b Institut Catal` a d’Oncologia, Institut d’Investigaci´o Biom`edica de Bellvitge, Barcelona, Spain Received 3 April 2007; received in revised form 30 July 2007; accepted 9 August 2007 Available online 5 September 2007

Abstract Although early vaccination is recommended in candidates for solid organ transplantation (SOT), consensual protocols do not yet exist. We applied an SOT vaccination protocol in the Hospital Clinic of Barcelona (Spain). Serology was performed before and after vaccination and compliance with the vaccination schedule was analysed during the period 2003–2004. Two hundred and thirty seven patients (72.9% male; mean age 56.31 years, range 19–72) were included. A total of 74.5% of subjects susceptible to hepatitis B virus infection responded to hepatitis B vaccination. Most patients were protected against hepatitis A, varicella, measles, rubella and mumps. The vaccine protocol was implemented satisfactorily and the administration of two courses of hepatitis B vaccine was shown to be effective. © 2007 Elsevier Ltd. All rights reserved. Keywords: Vaccines; Solid organ transplantation; Immune response

1. Introduction Immunosuppressed patients have a higher risk of suffering severe infections than immunocompetent subjects. Around 50–70% of recipients of solid organ transplants suffer microbial invasion during the first year posttransplant, with widely varying consequences [1]. The risk of acquiring infections and the possibility of preventing them through vaccination are closely related to the individual immune status, which in turn depends on the underlying disease, immunosuppressive therapies and the medico-surgical maneuvers associated with the transplant [2]. Some reports suggest that the infectious agent can cause graft rejection and that active immunization may be an effective protective strategy [3,4]. Studies on the efficacy, safety of vaccination schedules in patients in transplant programmes are scarce and differ according to country, period of administration, age and ∗ Corresponding author at: Beatriz Serrano Carro. Preventive Medicine Service, Adult Vaccination Centre, Hospital Clinic-IDIBAPS. Villarroel 170, 08036, Barcelona, Spain. E-mail address: [email protected] (B. Serrano).

0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.08.031

underlying pathology. For these reasons, there are, as yet, no protocols for routine vaccination of candidates for solid organ transplant (SOT), unlike the situation with hematopoietic stem cell transplantation receptors [5–7]. However, a series of criteria for the administration of vaccines in candidates for SOT is accepted [8–11]. (1) The time from inclusion of the patient in the waiting list to transplantation and should be taken advantage of, as early vaccination is more likely to achieve an adequate immune response. (2) Inactivated vaccines are not contraindicated either before or after transplant and are administered following the same guidelines as those for immunocompetent subjects, although the dose may sometimes be increased [12]. (3) Attenuated vaccines (MMR, oral polio, varicella-zoster, yellow fever, BCG and oral typhoid) are contraindicated in immunosuppressed subjects. (4) Serologic tests are recommended before and after vaccination, as they are useful to determine the vaccines needed and whether further doses may be necessary. (5) Although a subject may have been correctly vaccinated, in situations of imminent or substantial risk the administration of other prophylactic measures such as drugs or specific immunoglobulins should be considered. (6) Contacts and cohabitants should be vaccinated against influenza, measles,

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rubella, mumps, varicella and poliomyelitis and should avoid contact with the candidate for SOT if they suffer an infectious disease. (7) When vaccination is begun or reinitiated after transplant, adequate immunization and the reduction of possible adverse effects are critical. To achieve this, inactivated vaccines should not be administered until at least 6 months after the transplant. Attenuated vaccines are contraindicated until there are sufficient reports which guarantee their safety in transplanted subjects [13]. The objective of this study was to determine the degree of compliance and the immunity achieved after applying a vaccination protocol for candidates for SOT drawn up in the Adult Vaccination Centre of the Hospital Clinic of Barcelona during 2003–2004.

2. Methods In 2003, a vaccination protocol was drawn up in the Adult Vaccination Centre of the Hospital Clinic of Barcelona (AVCC) based on existing recommendations and updated as further information became available (Table 1). We retrospectively analysed a cohort of candidates for solid

organ transplantation who initiated the vaccination protocol between January 2003 and December 2004. Candidates for SOT are sent to the AVCC by the transplant units after analytic tests, including antibodies against hepatitis A, hepatitis B, measles, rubella, mumps and varicella. Patients without analytic tests are tested on the first visit to the AVCC. Patients are vaccinated according to the results of the serology and the individual vaccination history (vaccination centre records and medical history). The protocol is completed by further serological tests to determine whether the patient has been correctly immunized. For the hepatitis B virus, three doses of vaccine are administered. Serological tests are made to determine whether the patient has been correctly immunized and, if not, a new course of three doses is administered and the serological tests are repeated. In addition, serological tests were also made when possible in patients not receiving all the doses needed to complete the vaccination protocol. The Hospital Clinic of Barcelona is a reference centre for SOT, especially kidney transplants. However, most patients attending the AVCC for inclusion in the protocol were candidates for liver transplant, with only a small number of

Table 1 Vaccination protocol of candidates for solid organ transplantation

Adult Vaccination Centre, Hospital Clinic of Barcelona (initiated 2003 and updated). HB, hepatitis B; Td, tetanus–diphtheria; VZV, varicella zoster virus; Pneumo23, pneumococcal 23v polysaccharide; Hib, Haemophilus influenzae type b; HA, hepatitis A; MMR, measles–mumps–rubella; IPV, inactivated polio vaccine; PPD, purified protein derivative; tuberculin test. PVP (Pretransplant Vaccination Protocol): IgG antimeasles, rubella, mumps, varicella and hepatitis A; HB markers (IgG against core antigen and surface antigen). Ψ Vaccines administered based on the results of the serologic examinations and the vaccination history. If patient transplanted before completing protocol, vaccination postponed until 6 months after transplantation. # Requested before sending patient to Vaccination Centre. φ When titre of anti-HBs < 10 UI/ml. δ Administration of one vaccine or the other according to season (vaccine availability). Ω Dose included from March 2004. ς Reading at 72 h, repeat in 1 week if result negative. Ξ When anti-HBs negative repeat schedule at 0, 1, 2 months (40 ␮g); when anti-HBs positive continue as indicated. ∅ If it is necessary to administer a second course of hepatitis B vaccine, serology should be carried out at least 1 month after completing the course.

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candidates for kidney transplant. This is because most had been on dialysis before inclusion in the transplant programme and patients on dialysis or candidates for dialysis have another specific vaccination protocol drawn up by the AVCC. For this reason, most candidates for kidney transplant have already received the recommended vaccines and are not included in the study protocol. Study patients were obtained from the data base of the AVCC. The entry criterion was receiving the first dose of vaccine between January 2003 and December 2004 (baseline). Patients under 18 years of age, and those receiving vaccines outside the Hospital Clinic for whom no information was available were excluded. For each study subject, demographic (sex, date of birth and place of residence), clinical (type and date of transplant, death and date of death, disease motivating transplant) and vaccination (type of vaccine, number of doses, date of administration, date and results of serology) data were determined. Humoral immunity was measured using quantitative variables (IgG titres) in the case of antibodies against the surface antigen of the hepatitis B virus (anti-HBs) and qualitative variables (IgG positive or negative) for antibodies against measles, rubella, mumps, varicella and hepatitis A. Antibodies against the HBV core antigen (anti-HBc) and surface antigen (HBsAg) were determined before and after the vaccination schedule. The techniques used for these determinations were IgG rubella, HBsAg, anti-HBs, anti-HBc total and anti HVA total (Centaur System, Siemens). The respective cut-off points were: IgG antirubella ≥ 10.0 mUI/ml, HBsAg ≥ 50.0 mUI/ml, anti-HBs ≥ 10.0 mUI/ml, anti-HBc

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total ≥ 1.0 index value and anti-HAV total ≥ 20 mUI/ml. IgG VZV, measles and mumps (Vircell SL, Granada, Spain), with a cut-off point of ≥11 of index value. In the statistical analysis all immunity variables were treated as categorical considering titres of anti-HBs ≥10 mUI/ml as protective. Antibodies for the other vaccines included in the protocol were not examined in any analysis. The disease motivating the transplant was grouped in two categories: presence or absence of hepatitis C, as this disease has been reported to be associated with a worse response to hepatitis B vaccination [14]. From 40 years of age onwards, the immunogenicity of the hepatitis B vaccine falls to below 90% and after 60 years of age only 65–76% of adults develop protective antibodies [15]. The age of the patients in our study did not allow these cut-off points to be used and therefore patients were analysed according to tertiles (51 years and 60 years). The statistical analysis was carried out using the SPSS v.11 statistical package. A descriptive univariate analysis of the study population was made. Bivariate and multivariate analyses were made using the binary variable immunization against hepatitis B (immune = 1, not immune = 0) as the response variable. In the bivariate analysis the following variables were included; age, sex, type of transplant, accomplishment of transplant, immunosuppressive therapy, associated diseases, death and doses of vaccines received. The level of statistical significance was established at p < 0.05. The Chi2 test (Fisher’s exact test when the conditions of application of the Chi2 test were not fulfilled), the Mann–Whitney U test or the lineal trend test were used to compare categorical variables. Statistically significant variables in the bivariate

Fig. 1. Explanatory algorithm of the management of the patients.

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around 90% of patients. However, they were not available in 45% of patients not immunized against hepatitis B at baseline (Table 2). Two patients received a dose of the MMR vaccine and showed seroconversion. Of the three patients not immune to the VZV, two received two doses of the vaccine and showed seroconversion. Seventeen of the 21 patients not immune to hepatitis A were vaccinated (4 with 1 dose and 13 with 2 doses) and 13 responded to the vaccination (1 with 1 dose and 13 with 2 doses). With respect to protocol vaccines not examined in the final analysis, 184 doses of influenza vaccine, 215 doses of pneumococcal vaccine and 137 doses (booster) of polio were administered. Sixty-one patients received 2 doses of Haemophilus influenza type b vaccine and 148 received a single dose; 41 patients received a course of 3 doses of Td, 77 received 2 doses and 75 a single dose. In total, 116 patients (49%) out of the 237 patients initially included completed the vaccination protocol.

analysis were introduced into a logistic regression model for the multivariate analysis.

3. Results 3.1. Follow-up and losses Between January 2003 and December 2004, 237 patients began the SOT protocol. Demographic and clinical data and the type and doses received of vaccines were available for all patients. The algorithm in Fig. 1 explains the different stages in which the analyses were carried out and the number of patients analysed in each stage. 3.2. Sociodemographic and clinical characteristics Of the 237 patients, 72.9% (173) were male. The mean age was 56.3 years (range: 19–72). The mean age broken down by type of transplant was: kidney (mean 48.5 years), liver (56.2 years) and heart (mean 59.6 years). Statistically significant differences in age were observed according to type of transplant (heart versus kidney: p < 0.0001, heart versus liver: p = 0.023, liver versus kidney: p = 0.003) but differences according to sex were not found. Patients were candidates for liver 175 (73.8%), heart 38 (16.0%) and kidney 24 (10.1%) transplants. Ten point one percent (n = 24) of patients died in the hospital with a mean time of 7. 7 (DE = 6.5) months from baseline to death. By June 2006, 73.4% (n = 178) patients had been transplanted, with a mean time from baseline to transplant of 7 months. The mean time by type of transplant was: heart (8 months) liver (7 months) and kidney (6. 5 months).

3.4. Hepatitis B At baseline, 180 patients (75.9%) were not immune against HBV. Final serological data were available in 54.4% (n = 98), of which 73 (74.5%) had responded positively to vaccination. Forty-one patients responded to the first cycle of hepatitis B vaccination. Of the 63 patients who did not respond to the first cycle of hepatitis B vaccination and received a second course, serology was available in 50 patients, of whom 27 (54%) seroconverted. The bivariate analysis showed that the acquisition of antiHBs antibodies was related to the number of vaccine doses and age. There was a higher level of seroconversion in patients below 52 years of age, women and patients receiving more than one dose of hepatitis B vaccine, with the highest level occurring in patients receiving between two and four doses of vaccine (Table 3). No statistically significant associations were found for the remaining variables (sex, type of transplants, hepatitis C (+), death or transplant performed). The statistically significant variables in the bivariate analysis (age and number of doses of vaccines administered) and the variable hepatitis C (positive or negative) were included in the multivariate analysis. There was a greater risk of no response in patients aged 52–60 years compared to those aged <52 years (OR = 0.17; 95% CI (0.035–0.875), and patients aged

3.3. Serology and doses of vaccines administered Serological tests at baseline were carried out in 215 (90.8%) patients for measles, mumps, rubella and varicella, in 205 (86.5%) patients for hepatitis A and in 227 (95.8%) patients for hepatitis B. Most patients were immune to measles, rubella, mumps, varicella and hepatitis A. In contrast, 75.9% (n = 180) of patients were susceptible to hepatitis B virus infection. Final serological results for hepatitis A, varicella, measles, rubella and mumps were available in Table 2 Response to vaccination in patients susceptible in initial serology

Measles Mumps Rubella VZV HA HB

Total patients

Patients not immune in initial serology

Initial serology N (%)

Patients vaccinated N (%)

Losses

(+)

(−)

22 (9.2) 22 (9.2) 22 (9.2) 22 (9.2) 32 (13.5) 10 (4.2)

215 (90.8) 215 (90.8) 210 (88.6) 212 (89.4) 184 (77.6) 47 (19.1)

0 0 5 (2.2) 3 (1.6) 21 (8.9) 180 (75.9)

VZV, varicella zoster virus; HA, hepatitis A; HB, hepatitis B.

0 0 2 2 17 161

Final serology N (%) Losses

(+)

(−)

0 1 (33.3) 4 (19.0) 82 (45.6)

4 (80) 2 (100) 13 (76.4) 73 (74.5)

1 (20) 0 4 (23.6) 25 (75.5)

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Table 3 Bivariate analysis N (%)a

Reference category

OR

95% CI

Sex

98 (54.4)

Male

4.34

0.936–20.115

Age <52y vs. (52–60y) <52y vs. >61y. (52–60y) vs. >61y.

72 (54.9) 56 (56.0) 68 (52.7)

<52 y <52 y 52–60 y

0.22 0.25 1.13

0.057–0.861 0.058–1.071 0.393–3.219

0–1 0–1 2–4

6.66 0.20 0.03

0.366–121.272 0.022–1.746 0.004–0.230

HCV (+)

2.61

0.935–7.293

No. of dose vaccine (0–1) vs. (2–4) (0–1) vs. (>4) (2–4) vs. (>4)

95 (55.5) 97 (67.8) 107 (65.0)

HCV

98 (54.4)

Immunity against HVB at the end of the protocol in patients with initial serology negative. a % of patients analysed with respect to the total of candidates for SOT not immune to hepatitis B in the initial serology.

>60 years compared to those aged <52 years (OR = 0.19, although the 95% CI were not significant; 0.033–1.133). Patients receiving between two and four doses of hepatitis B vaccine responded more than those receiving more than five doses (OR = 0.03; 95% CI (0.003–0.237). Patients receiving less than two doses also responded more (OR=0.15), although the 95% CI were not significant; 0.007–2.920 (Table 4). 3.5. Comparison of patients completing the protocol and those lost to follow-up The 98 patients (51.6%) not immune to hepatitis B at baseline who completed the protocol were compared with the 82 patients (48.4%) who did not. Non-completers had a lower rate of transplantation (65.9 versus 80.6, p = 0.016) while completers had a higher percentage of deaths (15.9 versus 6.1, p = 0.034) and received a greater number of doses of hepatitis B vaccine (mean 4.0 versus 2.5, p < 0.001). No differences were observed with respect to age, sex, type of transplant, hepatitis C virus infection and immunosuppressive therapy (Table 5). Table 4 Multivariate analysis N (%)a

OR

95% CI

Sex Male Female

76 (77.6) 22 (22.4)

Reference 2.159

(0.365–12.762)

Age <52 y 52–61 y >61 y

30 (30.6) 42 (42.8) 26 (26.5)

Reference 0.174 0.195

(0.035–0.875) (0.033–1.133)

No doses hepatitis B 2–4 41 (41.8) 0–1 7 (7.1) >4 50 (51.0)

Reference 0.146 0.028

(0.007–2.920) (0.003–0.237)

HCV HCV + HCV −

Reference 3.323

(0.920–11.994)

59 (60.2) 39 (39.8)

Logistic regression. a % with respect to the 98 patients analysed.

4. Discussion Recent decades have seen a considerable increase in the number of immunosuppressed patients, including candidates for SOT [16]. Microbial invasion in the first year posttransplant is estimated to occur in 50–70% of transplanted patients [1], and is one of the main causes of premature death (18%) and graft failure [17]. Early vaccination has been suggested as an effective protective strategy in this group of patients [3]. However, information on the prevention of infection in candidates for SOT is scarce and varies widely [18–24]. For this reason, there are as yet no universal protocols of vaccination like that established in 1995 for receptors of hematopoietic stem cell transplantation [5] and thus it is difficult to compare protocols from different centres. Our results show that, with respect to the doses of vaccines administered, there was relatively good compliance of the protocol. The coverage of influenza vaccine was only 79%. However, this vaccine is frequently administered by primary health care centres [25], meaning that some patients have probably received the vaccine, leading to an underestimation of the coverage. This is not the case with the poliomyelitis vaccine. Only 58% of patients received the correct dose. This may be due to various reasons, including the smaller interest of doctors and patients in complying with the vaccination schedule, greater difficulties in administering the vaccine at the end of the protocol and problems of vaccine availability. The coverages achieved for the pneumococcal and tetanus–diphtheria vaccines were 90% and 81%, respectively. Only 61 (26%) patients received two doses of H. influenzae type b vaccine and 148 (62%) received a single dose. Until March 2004, the protocol recommended a single dose, with a second dose being included from this date onwards, explaining the lower coverage. The underlying diseases motivating transplantation are severe and prove fatal in a substantial proportion of patients. Ten percent of our patients died (probably an underestimate as this included only patients dying in the hospital). This may

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Table 5 Patients not immune to hepatitis b in the initial serology Non-completers N (%)

Completers N (%)

Number

82

98

Transplant Carried out Not carried out

54 (65.9) 28 (34.1)

79 (80.6) 19 (19.4)

Statistical test statistic (p-value)

5.843 (0.016)a

11.303 (0.001)b

Months 1st dose-transplant Before protocol 0–8 months >8 months after protocol Not transplanted

3 (3.7) 42 (51.1) 9 (11.1) 28 (34.1)

3 (3.1) 39 (39.8) 38 (38.8) 18 (18.4)

Death Yes No

13 (15.9) 69 (84.1)

6 (6.1) 92 (93.9)

Months 1st doses-death <4 4–8 >8 Survivors

6 (7.3) 4 (4.9) 3 (3.7) 69 (84.1)

0 (0.00) 1 (1.00) 4 (4.10) 93 (94.9)

4.478 (0.034)a

8.940 (0.003)b

2.50 (1.84)c 1.00 2.50 4.00

Doses HB vaccine P25 P50 P75

5.00 (1.75) 3.00 5.00 6.00

36.988 (0.000)b

Comparison of protocol completers and non-completers. a Test χ2 . b Lineal trend test. c Median and S.D.

provide a partial explanation of the relatively low compliance with the protocol and the lack of data. With respect to vaccines in which titles of antibodies were examined, 71.4% (13/17) of patients vaccinated against hepatitis A with final serology responded to vaccination, all having received two doses of vaccine. Although the sample is small, these results are similar to those of another study of immunosuppressed patients [26]. In contrast, in immunocompetent subjects, the proportion of responders is nearly 100% [27,28].

The two patients vaccinated against varicella developed antibodies after two doses of vaccine. Curiously, although only two of the five patients susceptible to rubella received a dose of MMR, at the end of the protocol four had acquired immunity against rubella (however, the cut-off point for rubella was 10 UI/ml and the two non-vaccinated patients who acquired immunity had titres of 11 UI/ml and 14 UI/ml, respectively). The hepatitis B vaccine was the main focus of the study as it is the disease where the greatest susceptibility exists. Vaccination achieved seroprotection in 75% of

Table 6 Studies on the immunogenicity of the hepatitis B vaccine in candidates for solid organ transplantation vaccinated before and after transplantation Author/vaccine

Time of vaccination

N (no. of cases)/transplant-diseased

Immunogenicity

Year/place

Razaman I [18] (invactiv.v. 40 ␮g) Dom´ınguez M [19] (invactiv. v. 40 ␮g) Watkins SL [20] (invactiv. v. 20 ␮g) Villeneuve [21] (invactiv. v. 20 ␮g) Horlander JC [22] (invactiv. v. 40 ␮g) Loinaz C [23] (invactiv.v. 40 ␮g) Chang SH [24] (invactiv.v. 40 ␮g) Serrano B (invactiv.v. 40 ␮g)

Pretransplant

152 (adults)/chronic hepatitis C.

3–4D: 109/152 (72%)

2002 EU-Turkey

Pretransplant

62 (adults)/hepatic tr.

3D: 22/62 (44%) 6D: 9/15 (60%)

2000 Spain

Pretransplant

2000 Canada

Pretransplant

140 (adults)/hepatic tr. (cirrhosis)

3D: 9/14 (64%; 152 mIU/ml) 39/42 (94%; 419 mIU/ml) 3D: 14/49 (49%) (9 months after 1st D) 3D: 37% (1–3 months after 3rd D)

2002 EU

Pretransplant

14 (children)/renal tr. 42 (children)/dialysis 49 (adults)/hepatic tr. (cirrhosis)

Posttransplant

140 (adults)/hepatic tr.

3D: 40%

1997 Spain

Posttransplant

19 (children)/renal tr.

17/19 at 10–15 months

2003 Korea

Pretransplant

98 (adults)/hepatic-renal-heart tr.

73/98 at end of vaccination protocol

2007 Spain

D, number of doses administered; HB, hepatitis B.

1999 USA

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patients susceptible at baseline, within the range of responders found by other studies of transplant patients, which varies between 37% and 94% [18–24] (Table 6). The wide range of responses observed depends on the underlying disease, the age, the vaccination schedule administered and the time from vaccination to the determination of antibody titres. Administration of a second course of three doses of hepatitis B vaccine in patients not responding to the initial vaccination schedule meant that 54% of these patients acquired protective titres of antibodies. This is in agreement with other studies of immunodepressed patients [19,29,30] and shows that in spite of the difficulties in achieving immunization against hepatitis B in some subjects, revaccination constitutes an effective strategy given the complications that a posttransplant infection would suppose [1,3,4]. Most published recommendations advise this type of schedule [11]. A substantial percentage of the patients studied lacked serological tests after administration of the hepatitis B vaccine. This could lead to bias in the final stages of the statistical analysis. Comparison of the 98 patients with and the 82 patients without final serology showed that in those without serology the percentage of deaths was greater than in completers (15.9% versus 6.1%) and death occurred earlier. Similarly, non-completers received less doses of hepatitis B vaccine (mean 2.5 versus 4.0) and underwent less transplants (65.9% versus 80.6%), possibly due to the earlier mortality, although when this occurred, the transplant was carried out closer to baseline. A possible limitation of the study was that the small sample size meant that analysis by type of transplant and statistical analysis of vaccines other than hepatitis B were limited. The results of this study, especially with respect to hepatitis B vaccination, suggest that consensual protocols for candidates for SOT can substantially reduce the number of candidates vulnerable to vaccine-preventable diseases and might reduce mortality and morbidity in this group of patients. Awareness of the benefits of vaccination in candidates for transplantation should be increased in patients, family members and medical professionals. Increased cooperation between transplant units and vaccination centres with respect to the initial serology could help to hasten the implementation of this type of protocol and increase the time available for compliance. In conclusion, a protocol for the vaccination of candidates for solid organ transplant achieved good results, especially with respect to hepatitis B vaccination, where the administration of a second course of vaccination in patients not responding to the first course of three doses was sufficient to rescue more than 50% of susceptible patients.

Acknowledgement We thank David Buss for technical help (english version).

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