Response to vaccination Antibody responses to vaccinations given

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Antibody responses to vaccinations given within the first two years after transplant are similar between autologous peripheral blood stem cell and bone marrow ...
Bone Marrow Transplantation (2001) 28, 775–781  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt

Response to vaccination Antibody responses to vaccinations given within the first two years after transplant are similar between autologous peripheral blood stem cell and bone marrow transplant recipients MK Gandhi1, W Egner2, L Sizer1, I Inman1, M Zambon3, JIO Craig1 and RE Marcus1 1

East Anglian BMT Unit, Addenbrooke’s Hospital, Department of Haematology, University of Cambridge; Cambridge, UK; 2Protein Reference Unit and Department of Immunology, Northern General Hospital, Sheffield, UK; and 3PHLS Central Public Health Laboratory, London, UK

Summary: As a consequence of the significantly larger inoculum of lymphoid cells present in peripheral blood stem cell (PBSC) harvests compared to bone marrow (BM), it is possible that autoPBSCT recipients may have an earlier and/or enhanced response to vaccines. Until data to confirm this become available, the European Blood and Marrow Transplantation Association (EBMT) recommend that all transplant recipients be immunized in the same way regardless of stem cell source. We performed a prospective study comparing serological responses to influenza, pneumococcal polysaccharide and tetanus toxoid vaccines between autoPBSCT with autoBMT recipients. Antibody responses in sibling HLA-matched allogeneic BMT (alloBMT) survivors were also evaluated. All vaccines were administered within the first 2 years after stem cell transplantation. Fifty patients were enrolled. The time of vaccination after transplant was similar between autoPBSCT (mean 11 months for each vaccine) and autoBMT recipients (mean 12 months except 13 months for tetanus toxoid) (P = NS). Serological responses were poor and no significant difference in response to any of the vaccines used was seen between the three transplant cohorts. We provide no evidence that current EBMT guidelines be modified. Large prospective vaccine studies are needed to address the issue more fully. Bone Marrow Transplantation (2001) 28, 775–781. Keywords: influenza; pneumococcal; tetanus; vaccine; autoPBSCT; alloBMT

After autologous and allogeneic stem cell transplantation, immune reconstitution may be more rapid if peripheral blood stem cells (PBSC) rather than bone marrow (BM) are re-infused.1–3 Transfer of humoral and cell-mediated immunity via the graft has been documented,4–7 suggesting Correspondence: Dr MK Gandhi, Box 234, Level 3, Department of Haematology, Addenbrooke’s Hospital, Hills Rd, Cambridge, CB2 2QQ, UK Received 4 June 2001; accepted 22 August 2001

that differentiated antigen-selected lymphocytes in the graft may be a significant source of post-transplant T and B cells. Because of the significantly larger inoculum of lymphoid cells infused during PBSCT,8 it is possible that PBSCT recipients may have an earlier and/or enhanced response to vaccines. The majority of data available so far on post transplant immunization are from BMT recipients. We performed a prospective study comparing serological responses to influenza, pneumococcal and tetanus toxoid vaccines in autologous PBSCT (autoPBSCT) with autologous BMT (autoBMT) recipients. Antibody responses in sibling HLAmatched allogeneic BMT (alloBMT) survivors were also evaluated. All vaccines were administered within the first 2 years after stem cell transplantation. The time of vaccination after transplant was similar between autoPBSCT (mean 11 months for each vaccine) and autoBMT recipients (mean 12 months except 13 months for tetanus toxoid) (P = NS). Fifty patients were enrolled.

Materials and methods Patients Between 1994 and 1997, 50 SCT patients (29 autoPBSCT, 12 autoBMT and nine alloBMT) entered the study. All patients provided informed consent. Exclusion criteria were ongoing infections, disease relapse, administration of intravenous immunoglubulin in the 3 months prior to vaccination, known or suspected allergy to components of the vaccine, and in the case of alloBMT the use of ongoing immunosuppressive therapy for graft-versus-host disease (GVHD). All vaccines were administered after at least 5 months and within 2 years after stem cell transplantation. Patients were not re-immunized with tetanus toxoid if they had been vaccinated within the last 5 years. There were 22 females and 28 males, with a mean age of 43.1 (range 15 to 63) years. Within transplant cohorts, mean ages were respectively, 47.4 years (autoPBSCT), 34.9 years (autoBMT), and 40.7 years (alloBMT). There was a significant difference in age between autoPBSCT vs autoBMT (P = 0.03, unpaired Student’s t-test), but not between

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autoSCT (autoPBSCT and autoBMT combined) vs alloBMT. Patient characteristics, including vaccines administered by transplant subtype, are summarized in Table 1. Cell mobilization, preparative regimens and GVHD prophylaxis Transplantation procedures were performed as per previously published protocols.9–11 Table 1 summarizes the preparative regimens used. Intravenous cyclophosphamide and G-CSF (5 ␮g/kg subcutaneously) was used for PBSC mobilization and all alloBMT recipients had standard GVHD prophylaxis with methotrexate and cyclosporin A.11 Vaccines Influenza: A single-dose standard trivalent subunit influenza vaccine (Influvac: Pasteur Merieux, Maidenhead, UK) active against the relevant season’s influenza strains (against H1N1, H3N2, and influenza B) was administered. A single batch was used for each season. Mean time of vaccination following SCT was: 11 months for autoPBSCT (s.d. 5.5); 12 months for autoBMT (s.d. 5.8); 16 months for alloBMT (s.d. 2.9); for autoPBSCT vs autoBMT P = 0.76 and for autoSCT vs alloBMT P = 0.032. Pneumococcus: A non-conjugated polysaccharide 23-valent subunit vaccine (Pneumovax II: Merck, Sharp and Dohme, Hertfordshire, UK) was used. Mean time of vaccination following SCT was: 11 months for autoPBSCT (s.d. 5.3); 12 months for autoBMT (s.d. 5.5); 16 months for alloBMT (s.d. 3.7); for autoPBSCT vs autoBMT P = 0.64 and for autoSCT vs alloBMT P = 0.005.

Table 1

Patient characteristics AutoPBSCT (29)

AutoBMT (12)

AlloBMT (9)

34.9 (15–52)

40.7 (26.7–50.5)

10:19

8:4

4:5

— 12 6 11

8b 4 — —

7c 1 — 1

Vaccine Influenza (%) Pneumovacc (%) Tetanus (%)

24 (83) 29 (100) 24 (83)

10 (83) 11 (92) 9 (75)

Preparative regimen BEM Melphalan BuCy TBI/Cyclo

25 1 — 3

7 1 — 4

Mean age (years)a Sex (F:M) Diagnosis Leukaemia NHL HD Myeloma

47.4 (21–60.2)

8 (89) 9 (100) 8 (89) — — 2 7

a Mean ages were compared between autoPBSCT vs autoBMT (P = 0.03) and autoSCT vs alloBMT (P = NS), unpaired Student’s t-test. b One chronic myeloid leukaemia (CML), five acute myeloid leukaemia (AML), two acute lymphoblastic leukaemia (ALL). c Four AML, three CML.

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Tetanus toxoid: A single administration of Diftavax (Pasteur Merieux) was given. Tetanus toxoid immunisation within the preceding 5 years was a contra-indication to booster immunisation with the same vaccine. Mean time of vaccination following SCT was: 11 months for autoPBSCT (s.d. 4.8); 13 months for autoBMT (s.d. 5.2); 16 months for alloBMT (s.d. 3.7); for autoPBSCT vs autoBMT P = 0.21 and for autoSCT vs alloBMT P = 0.004. The vaccines were administered by deep intramuscular injection at separate sites. No significant adverse reactions were recorded. Specific antibody assays and definitions of serological response Assays were taken immediately prior to vaccination (to assess susceptibility) and then again 28 days after vaccination in order to determine whether there had been a response, and finally at 6 months to see if the response had been maintained. Influenza: Anti-influenza antibodies (expressed as haemaggluttination inhibition (HI) titres) were performed by standard microtitre technique.12 We used conventional criteria to define a humoral response to influenza vaccination: a four-fold rise in titre when HI antibodies were re-tested 1 month after vaccination, and secondly an HI titre greater than or equal to 40 was required. This threshold has been shown in numerous studies to correlate with protection against influenza infection13–15 in immunocompetent individuals. Pneumococcus and tetanus toxoid: Total IgG and IgG2 subclass antibodies to pneumovax II, and the tetanus assay were measured by enzyme-linked immunosorbent assays (ELISA).16 The tetanus assay was calibrated in milli-international units (mIU)/ml against the WHO international reference preparation 75/589 (National Institute of Biological Standards and Control (NIBSC), Potters Bar, UK). In the absence of a reference preparation anti-pneumococcal antibodies (APA) were reported in arbitrary ELISA units. One ELISA unit of IgG APA is not equivalent to 1 ELISA unit of IgG2 APA. Titres below the limit of sensitivity of the assays were designated as 6 IgG2 (APA) units, 12 IgG (APA) units and 12 mIU/ml (tetanus) for statistical analysis. Pneumovax II is a 23-valent vaccine of varying immunogenicity. As our interest was in demonstrating whether transplant recipients were able to mount a response to any component of the vaccine, we measured global and not serotype-specific responses. Failure to mount an overall antibody response indicated immunodeficiency. For pneumovax II and tetanus toxoid vaccinations, responses were subdivided into four-fold or greater increments in titre (⭓4fold), between two- and 3.9-fold (2–3.9-fold) and less than two-fold (⬍2-fold). Long-term protective antibody titres to tetanus were defined as ⬎100 mIU/ml. Baseline immune status Immune status was assessed immediately prior to vaccination. Immunoglobulin levels (IgG, IgA and IgM) levels

Antibody response to early vaccination after autoPBSCT MK Gandhi et al

were measured by nephelometry. Lymphocyte subsets were analysed using lysis-II software on a FACScan cytometer (Becton Dickinson, Oxford, UK). Delayed type hypersensitivity (DTH) responses were analysed using multi-test cellmediated immunity (CMI) skin testing kits (Pasteur Merieux). Glycerine was used as a control. Injections were applied to the volar aspect of the forearm and read at 48 h by measuring the mean weal diameter in two directions at 90° to each other.

patients (12 autoPBSCT, three autoBMT, six alloBMT) had DTH skin tests pre-vaccination. Twenty-five controls were skin tested (Table 3). Skin test positivity (defined by number of antigens ⬎2 mm mean weal diameter) was significantly reduced in all patient groups pre-vaccination (autoPBSCT P ⬍ 0.01, alloBMT P = 0.02, autoBMT P = 0.014) compared to the controls, and most patients in all groups were anergic (no positive antigens).

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Baseline susceptibility Control samples For comparison, we performed specific antibody assays on unvaccinated healthy individuals. Seventeen healthy volunteers and eight healthy bone marrow donors (median age 35.5 (range 25–57.4) years; eight males and 17 females) were tested. Statistical analysis Immunophenotyping data, immunoglobulin levels, DTH responses and baseline antibody titres were compared with controls, and between transplant types (autoPBSCT vs autoBMT; and autoSCT (autoPBSCT and autoBMT combined) vs alloBMT), using the independent Student’s t-test or Fisher’s exact test where stated. Both post-vaccination antibody responses and time of vaccination post transplantation, were compared between transplant types in 2 × 2 contingency tables using Fisher’s exact test. Spearman’s rank correlation was used to compare vaccine responses to age at transplantation, gender and diagnosis. All statistical analysis was performed using SPSS for Windows software.

Results Baseline immunological data Median immunoglobulin levels of all cohorts combined (IgG 8.38 g/l, range 3.52–24.2 (normal range (NR) 6.0– 13.0); IgA 1.00 g/l range 0.07–3.71 (NR 0.8–3.7), and IgM 0.70 g/l range 0.32–3.59 (NR 0.4–2.2)) were in the majority of patients, within the normal adult reference range. There was no significant difference between transplant categories, or between healthy controls (data not shown). Immunophenotyping data were available in 20 controls, 23 autoPBSCT (median 9 months post transplant), 11 autoBMT (median 13 months post transplant) and seven alloBMT (median 15 months post transplant). Samples from the remaining nine patients and five controls were unsuitable for further analysis. Table 2 summarizes the data. Total lymphocyte counts were significantly reduced in the autoPBSCT and autoBMT but not in alloBMT cohorts compared to controls. All cohorts had a CD4+ T cell lymphopenia. CD19+ B cells and CD3⫺/16+ and CD3⫺/56+ NK cells were not significantly reduced in any cohort. In patients with myeloma, NHL and HD immunophenotypes were not significantly different from each other (data not shown). In order to assess TH1 inflammatory responses, 21

In order to assess susceptibility to infection prior to vaccination, baseline pre-vaccination antibody titres were taken in patients and compared to healthy volunteer controls. Influenza: Prior to influenza vaccination, baseline HI titres were taken in 36 study patients, and compared with 25 healthy volunteer controls. In both study patients and controls, prior to vaccination the majority of cases were susceptible to all three strains (20/36 and 17/25 no protection, 16/36 and 7/25 protection against one or two strains, 0/36 and 1/25 protection against all three strains, respectively). There was no significant difference in susceptibility between patients and controls, and between transplant categories. Pneumococcus: Respectively, 25 and 23 out of 25 controls had positive total IgG and IgG2 APA titres (median titres 20.9 and 82.3 ELISA units). Prior to administration of Pneumovax all transplant cohorts had lower titres than the healthy controls (IgG: autoPBSCT P ⬍ 0.001, autoBMT P ⬍ 0.005, alloBMT P = 0.001; IgG2: autoPBSCT P ⬍ 0.001, autoBMT P ⬍ 0.006, alloBMT P = 0.001). There was no significant difference between transplant subtypes. Tetanus toxoid: Ninety-six percent of the control population had titres ⬎100 mIU/ml. All transplant cohorts had pre-vaccination anti-tetanus titres significantly lower than the controls (autoPBSCT P ⬍ 0.001, autoBMT P ⬍ 0.04, alloBMT P = 0.001). Antibody responses No adverse events were reported that could be attributed to vaccination. Figure 1 summarizes the antibody response to vaccination. Influenza vaccination: After influenza vaccination, a protective serological response against only one or two strains was seen in 21% of autoPBSCT recipients, and 13% had a response against all three strains. Similarly, 20% of autoBMT patients had a one or two strain response and 10% a response vs all three. There was no statistical significance between autologous stem cell transplant subtypes. No patients with allogeneic bone marrow had any response at all. The difference between autoSCT (autoPBSCT and autoBMT combined) and allogeneic transplant was not statistically significant. Overall, there was a response against only one or two strains in 16.7% (or 7/42 patients) and a response against all three strains observed in 1% (or 4/42patients). When protective humoral responses occurred, HI titres were maintained at 6 months. There was Bone Marrow Transplantation

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Table 2

Baseline immunological data taken pre-vaccination: immunophenotyping results

Lymphocyte subtypes mean (s.d.) × 109/l

CD3+ T cells (NR 1.0–2.8)

CD3+/4+ T cells (NR 0.3–1.4)

CD3+/8+ T cells (NR 0.2–0.9)

CD3+/45ROhi CD3+/45RAhi RAhi/ROhi T cells T cells ratio T cells

CD3+/HLA- CD19+ B cells CD3+/16+ DR+ (NR 0.1–0.5) and CD3−/56+ T cells NK cells

AutoPBSCT (n = 23)

0.96 (0.6) P = 0.02

0.29 (0.2) P ⬍ 0.001

0.51 (0.34)

0.56 (0.4)

0.56 (0.4)

1.04 (0.57) P = 0.02

0.41 (0.5) P = 0.014

0.18 (0.1)

0.13 (0.1)

AlloBMT (n = 7)

0.99 (0.6)

0.35 (0.11) P = 0.0004

0.32 (0.17)

0.6 (0.43)

0.57 (0.19)

1.47 (0.4)

0.23 (0.09)

0.24 (0.1)

0.22 (0.21)

autoBMT (n = 11)

0.62 (0.25) P ⬍ 0.001

0.24 (0.11) P ⬍ 0.001

0.29 (0.16)

0.35 (0.15) P = 0.02

0.39 (0.22) P ⬍ 0.001

1.1 (0.49) P ⬍ 0.001

0.19 (0.15)

0.26 (0.14) P = 0.04

0.11 (0.05)

Controls (n = 20)

1.37 (0.45)

0.85 (0.32)

0.34 (0.14)

0.68 (0.29)

1.05 (0.46)

1.7 (0.87)

0.11 (0.12)

0.17 (0.09)

0.18 (0.14)

Only significant P values (unpaired student’s t-test vs controls on log-transformed data) are shown. NR = normal range; s.d. = standard deviation.

Table 3 Baseline immunological data taken pre-vaccination: CMI skin test responses Control (n = 25)

AutoPBSCT (n = 12)

AutoBMT (n = 3)

AlloBMT (n = 6)

No. positive for tetanus Tetanus mean weal size (mm)

18

3

0

1

3.1

1.3

0

0.64

No. positive for tuberculin

13

2

0

0

Tuberculin mean weal size (mm)

2.2

0.42

0

0

Skin tests were impaired in all groups pre-vaccination (autoPBSCT P ⬍ 0.01, autoBMT P = 0.014, alloBMT P = 0.02, Fisher’s exact test) compared to the controls.

no significant correlation between the antibody response and diagnosis, age or patient’s sex. There was no significant difference in the relative immunogenicity between vaccine sub-units. Pneumococcal polysaccharide vaccine: After pneumococcal polysaccharide vaccine in autoPBSCT patients a serological response occurred to total IgG in 45% (2–3.9-fold: 17%, ⭓4-fold: 28%) and IgG2 in 24% (2–3.9-fold: 14%, ⭓4-fold: 10%). With autoBMT, total IgG responses occurred in 18% (all ⭓4-fold) and to IgG2 in 9% (all ⭓4fold). The difference between autologous transplant types did not reach statistical significance. One-third of alloBMT patients had a 2–3.9-fold response by IgG to pneumovax, and another third a ⭓4-fold. No alloBMT recipients had any IgG2 response. The difference between autoSCT and allogeneic transplant was not statistically significant. We were unable to assess the 6 month maintenance of serological response in two autoPBSCT and one autoBMT recipients. Otherwise responses were maintained in all but two cases (one autoPBSCT and in one alloBMT patient). There Bone Marrow Transplantation

was no significant correlation between the antibody response and diagnosis, age or patient’s sex. Tetanus toxoid vaccination: After tetanus toxoid vaccination, a serological response occurred in 38% (2–3.9-fold: 4%; ⭓4-fold: 33%) of autoPBSCT and 11% (all ⭓ 4–fold) of autoBMT survivors (P = 0.127). With alloBMT, 13% of patients had a 2–3.9–fold response, and 38% a ⭓4-fold response (any response 50%). There was no significant difference in response between autoSCT and allogeneic transplant recipients (P = 0.41). We were unable to assess the 6 month maintenance of serological response in one autoPBSCT patient. Otherwise responses were maintained in all but two cases (one autoPBSCT and in one alloBMT patient). There was no significant correlation between the antibody response and diagnosis, age or gender.

Discussion We undertook this study in order to determine whether autoPBSCT recipients had enhanced serological responses to vaccination compared to patients undergoing autoBMT. Improved vaccine responses might be predicted as a consequence of the significantly larger inoculum of lymphoid cells within PBSC rather than bone marrow.1,8 The EBMT currently recommend that all transplant recipients be immunized in the same way regardless of stem cell source.17 We performed a prospective study comparing serological responses to influenza, pneumococcal polysaccharide and tetanus toxoid vaccines between autoPBSCT with autoBMT recipients. Responses in sibling HLA-matched alloBMT survivors were also analysed. Fifty patients were enrolled. All vaccines were administered within 2 years after stem cell transplantation. Time of vaccination after transplant was similar between autoPBSCT (mean 11 months for each of the vaccines) and autoBMT recipients (mean 12 months except 13 months for tetanus toxoid) (P = NS). No adverse events were reported following vacci-

Antibody response to early vaccination after autoPBSCT MK Gandhi et al

120

Influenza vaccination

120 100

% responders

% responders

100 80 60 40 20 0

80 60 40 20

autoPBSCT

autoBMT

0

alloBMT

autoPBSCT

P = 1.00 120

Total IgG response to Pneumovacc

120

alloBMT

IgG2 response to Pneumovacc

100

% responders

% responders

autoBMT

P = 0.22

100 80 60 40 20 0

779

Tetanus toxoid vaccination

80 60 40 20

autoPBSCT

autoBMT

alloBMT

P = 0.16

0

autoPBSCT

autoBMT

alloBMT

P = 0.41

Figure 1 Antibody response to vaccination. (쐽) No response (no protective antibody titre response to any of three strains for influenza; ⬍2-fold rise in antibody titre for both pneumovax and tetanus toxoid). (쏔) Any response (protective antibody titre response to ⭓1 strain for influenza; ⭓2-fold rise in antibody titre for both pneumovax and tetanus toxoid). P values calculated by Fisher’s exact test.

nation. No significant difference in response to any of the vaccines used was seen between the three transplant cohorts. Although differences in age and diagnostic categories were present between groups, multivariate analysis failed to show a correlation between the humoral response and diagnosis, gender or patient’s age at transplant. Antibody responses were most impaired after influenza vaccination. There were no responses in the allogeneic cohort. Poor serological responses were also seen by Engelhard et al.18 In their study, 48 patients (35 allogeneic T cell-depleted and 13 autoBMT recipients received a twodose influenza vaccine regimen at a time interval ranging from 2 months to 7 years post SCT. The authors concluded that the only factor predictive of a humoral response was the time interval between vaccination administration and SCT. We cannot rule out the possibility that HI titres may have provided an insufficient assessment of the vaccine’s ability to confer partial protection and/or reduce severity of infection. The poor serological response to influenza vaccination observed supports the view that alternative methods such as chemoprophylaxis,19 or potentiation of anti-influenza immunity with adjuvant20,21 or by immunization of

donors prior to stem cell harvesting should be prospectively studied. Immediately prior to vaccination, baseline anti-pneumococcal antibody titres were significantly reduced compared to normal controls. Similar findings have been reported by Hammarstrom et al22 in allograft recipients, although they were unable to detect a difference in pneumococcal antibodies between autoBMT patients vs controls. They did not study autoPBSCT patients. Overall, 43% of recipients in our study mounted an antibody response to pneumovax. However, these were predominately observed when measuring total IgG (and were largely not seen for IgG2) and the responses were thus ‘immature’. IgG2 responses were absent in alloBMT patients. Similar results have been reported after alloBMT in children.23 Unconjugated vaccines are weak immunogens, and responses to polysaccharide antigens are unlikely before 2 years. In adults a similarly poor response to pneumoccocal polysaccharide vaccine after alloBMT was observed by Parkkali et al,24 and they further found that there was no difference in response between recipients randomized to receive vaccine at 8 vs 20 months respectively. However, Avanzini et al25 Bone Marrow Transplantation

Antibody response to early vaccination after autoPBSCT MK Gandhi et al

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observed that antibody responses do improve with time if vaccination is administered beyond 2 years. Before 2 years additional chemoprophylaxis may need to be considered and lifelong penicillin V is currently recommended for certain patient categories.17,26 Eight of 24 autoPBSCT recipients had a complete response to tetanus toxoid, compared to only one of nine patients after autoBMT (P = NS). Our results are consistent with those observed by Chan and co-workers.27 They compared multi-dose schedule HiB and tetanus toxoid vaccination (given at 3, 6, 12 and 24 months) to 17 autoBMT and 10 autoPBSCT recipients. No significant difference in antibody levels or response was detected until 2 years. However, anti-tetanus IgG antibody levels were significantly higher in autoPBSCT patients compared to autoBMT before (borderline significance P = 0.051) and after the 24 month inoculation (P = 0.006). Both their and our studies are small and we cannot rule out a type 2 statistical error, ie that a genuine difference in antibody response is present before 2 years but was not detected as a result of study size. We estimate that to detect a 20% difference in vaccine response approximately 120 autoSCT survivors will need to be enrolled. Clearly, large prospective studies are needed to address the issue more fully. In all cohorts, more than 75% of assessable vaccineresponding patients maintained their antibody titres over 6 months. This suggests that the responses seen were not transient, and in the case of tetanus toxoid and pneumovax may have been due to successful re-stimulation of an anamnestic memory response. Although there is a larger T cell inoculum present within PBSC grafts relative to BM, it remains unclear whether there are qualitative differences in the T cells contained in the stem cell harvest. Following transplant, analysis of lymphocyte subsets taken prior to vaccination demonstrated a significant reduction in CD4+ T cells compared with controls for both autoBMT and autoPBSCT. However, there was no significant difference in CD4+ T cells between the two transplant cohorts. This may have contributed to our subsequent inability to demonstrate any significant difference in serological response to two different T celldependent vaccines (influenza and tetanus toxoid) and a T cell-enhanced vaccine (pneumovax),28 between autoBMT and autoPBSCT recipients. Therefore, unless further data become available from large prospective vaccine studies, there is no evidence that current EBMT guidelines be modified. Acknowledgements The Kay Kendall Fund assists work performed in this Department. MK Gandhi is a Leukaemia Research Fund Clinical Research Fellow. We would like to thank Coral Howlett and Patricia Barker for assisting with data collection, and Dr Jane Greatorex for kindly reviewing the manuscript.

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