Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia

Vaccine 19 (2001) 1671– 1677 www.elsevier.com/locate/vaccine

Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia A. Hartkamp a,1, A.H.L. Mulder b, G.T. Rijkers c, H. van Velzen-Blad b, D.H. Biesma a,* b

a Department of Internal Medicine, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands Department of Medical Microbiology & Immunology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands c Wilhelmina Childrens’ Hospital, Utrecht, The Netherlands

Received 11 November 1999; received in revised form 16 October 2000; accepted 19 October 2000

Abstract Although vaccination against Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae type b (Hib) is recommended for immunocompromised patients, such as patients with B-cell chronic lymphocytic leukaemia (B-CLL), its protective effect is questionable. We studied antibody responses to pneumococcal polysaccharide vaccine (Pneumovax-23®) and to conjugated H. influenzae type b-vaccine (Act-Hib®) in 25 patients with B-CLL. After vaccination, the number of patients with antibody levels in the protective range against pneumococcal serotypes and H. influenzae b increased from 9 (38%) to 12 (50%) of 24 patients and from 8 (35%) to 11 (48%) of 23 patients, respectively. The patients with adequate antibody response to Pneumovax-23® and Act-Hib® had significantly less advanced stages of B-CLL, higher gammaglobulin levels, total IgG-levels and IgG-subclasses 2 and 4 levels, and lower levels of soluble CD23. Consequently, vaccination with these vaccines should be given as soon as the diagnosis of B-CLL is made, early in the course of the disease with determination of post-vaccination antibody levels. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Chronic lymphocytic leukaemia; Immunisation; Soluble CD23

1. Introduction Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in Europe and the United States of America. The malignant clone is of B-cell lineage in more than 95% of the cases. Although CLL affects mainly elderly (\50 years), life expectancy is relatively high (about 150 months in patients with CLL

* Corresponding author. Tel.: +31-30-2507357; fax: + 31-302523741. E-mail address: [email protected] (D.H. Biesma). 1 Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht (UMCU), F02.126, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Tel.: + 31-30-2507357; fax: +31-30-2523741.

Rai-0) [1,2]. Respiratory infections are frequently observed in patients with B-CLL due to hypogammaglobulinaemia and defective specific antibody responses resulting in relatively high morbidity and mortality [3–6]. Protection against serious and fatal infectious complications could be provided by active immunisation, but questions have been raised about the efficacy of vaccinations in patients with acquired immunodeficient states as in B-CLL [7,8]. Previous studies on immunisation of patients with malignant diseases with or without chemotherapy have yielded large differences in both efficacy and immunogenicity [9–12]. We studied antibody responses to pneumococcal polysaccharide capsular antigens (Pneumovax-23®) and conjugated Haemophilus influenzae type b-vaccine (ActHib®) in 25 patients with B-CLL, and tried to relate vaccine responses to disease progression for which sCD23 is considered a suitable marker [13].

0264-410X/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 0 ) 0 0 4 0 9 - 6

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2. Patients and methods

2.1. Patients Twenty-five patients (18 males and seven females) with immunophenotypically proven B-CLL were included; their mean age (9SD; range) was 70.49 7.9 years (range 50–84). The mean duration of disease ( 9 SD; range) was 49.4953.0 months (range: 6 –240). The stage of B-CLL was expressed according to Rai [2]: 10 patients were classified as Rai-0, 5 patients as Rai-1, six patients as Rai-2, and 4 patients as Rai-4. Eight patients (32%) had been treated previously with chemotherapy, but no patient had received chemotherapy during a period of at least three months prior to vaccination. None of the patients received prior vaccination with Pneumovax-23® or Act-Hib®. Data concerning prior vaccination with tetanus toxoid were obtained by interview. Eleven (44%) of 25 patients had been immunised with tetanus toxoid, eight of them received at least three doses, three of them at least a single dose. Two of the tetanus-vaccinated patients had been immunized with tetanus toxoid less than 5 years before the study period, one more than 5 years but less than 10 years. The remaining eight patients had been immunized with tetanus toxoid more than 10 years before the study period. The patients received simultaneously an intramuscular injection of a 23-valent pneumococcal polysaccharide vaccine (Pneumovax-23®; MSD; USA) and a conjugated H. influenzae type b-vaccine (Act-Hib®, Pasteur-Merieux Laboratories, Lyon, France). Patients were monitored for 15 min after injection for any immediate reaction. Local and systemic reactions were followed during 3 days after vaccination by the patients who noted any events in a structured questionnaire.

2.2. Methods At study-entrance, blood samples were taken to determine whole blood count including leukocyte differentiation, gammaglobulin-fraction, total levels of IgA, IgM and IgG, including IgG-subclasses, and soluble CD23-levels. Hypogammaglobulinaemia was defined as a gammaglobulin level 56.2 g/l. Normal ranges of serum immunoglobulins in our laboratory were defined as IgG, 7.0 –15.0 g/l; IgA, 0.5 – 4.0 g/l; and IgM, 0.4 –2.3 g/l. In one patient, paraproteinaemia of IgG-kappa was observed which made determination of gammaglobulinand total IgG-levels unreliable. Soluble CD23-concentrations were measured using Medgenix EASIA™ assay (Biosource, Fleurers, Belgium). Serum samples for determination of pre-vaccination and post-vaccination antibody titres against S. pneumoniae, H. influenzae type b and tetanus-toxoid were obtained at the day of vaccina-

tion (day 0) and 3 weeks after vaccination (day 21) and were stored at − 70°C for simultaneous analysis. Specific IgG-antibody titres against pneumococcal polysaccharide of serotypes 3, 4 and 9 and to the H. influenzae type b capsular polysaccharide polyribosylribitol phosphate were determined in the laboratory of G.T.Rijkers (Wilhelmina Children’s Hospital, University Medical Centre, Utrecht) by ELISA as described previously [14]. Pre- and postimmunisation samples were preincubated with excess (50 mg/ml) pneumococcal common cell wall polysaccharide (CPS) overnight at 4°C before analysis to block anti-CPS antibodies [15,16]. Serum from a normal non-vaccinated adult was included in each ELISA run to control for interassay variability. Antibody concentrations in patient samples were calculated using a reference adult hyperimmune plasmapool which contains 1.72 mg/ml anti-pneumococcal serotype 3, 17.1 mg/ml anti-serotype 4, 6.3 mg/ml anti-serotype 9V antibodies, and 27.2 mg/ml IgG anti-Hib [17,18]. Antitetanus toxoid IgG antibody titres were determined in the laboratory of G.T. Rijkers as described [19] with minor modification (anti-human IgG developing antibody). Patients were considered to have protective antibody titres against S. pneumoniae when at least two of the three tested serotype specific pneumococcal antibody titres were higher than 20% of the levels in the reference plasmapool (corresponding to threshold antibody levels of 0.34 mg/ml (serotype 3), 3.41 mg/ml (serotype 4) and 1.26 mg/ml (serotype 9V). A response to Pneumovax® was defined as having a two-fold or more increase in specific antibody titres together with post-vaccination levels 20% for at least two of the three tested pneumococcal polysaccharide capsular antigens. Pre-vaccination anti-Hib IgG-levels \1 mg/ml were considered sufficient. A response to Act-Hib® was defined as having a fourfold or more increase in specific IgG anti-Hib titres together with post-vaccination levels \ 1 mg/ml. A two-fold or more rise in specific anti-tetanus toxoid IgG antibody levels was considered as a positive response.

2.3. Statistics Statistical analyses were performed by using Fisher’s exact test, Wilcoxon-test or Student’s t-test as indicated. P values B 0.05 were considered statistically significant.

3. Results

3.1. Antibody response to pneumococcal polysaccharide 6accine One patient was excluded from the analysis because gammaglobulin therapy was started during the course of the study; a total of 24 patients were evaluable for

A. Hartkamp et al. / Vaccine 19 (2001) 1671–1677

analysis of specific antibody responses after pneumococcal polysaccharide vaccination. Prior to vaccination, specific antibody titres considered to be in the protective range against S. pneumoniae were present in nine (38%) of the 24 patients. In two (22%) of these nine patients, an adequate response to vaccination was observed. In another three (33%) of these nine patients, pre-vaccination specific antibody titres were high, exceeding 50% of the reference pool. After vaccination, antibody titres did increase but less than two-fold. Because of the high pre-vaccination titres it would be inappropriate to classify these patients as non-responders and therefore they were left out of subsequent analysis. In the other four of these nine patients no response after vaccination was observed. Low pre-vaccination specific antibody titres to S. pneumoniae were present in 15 patients; 3 (20%) of these patients had an adequate response to Pneumovax-23®. The other 12 patients were qualified as non-responders. Thus, a total of five (22%) out of 24 patients responded on Pneumovax® vaccination. Vaccination with pneumococcal polysaccharide vaccine led to an increase in the percentage of patients with sufficient antibody levels

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against S. pneumoniae from 38% (nine of 24 patients) to 50% (12 of 24 patients). Clinical and laboratory data of the responder-group were compared to the patients who did not respond on vaccination (the non-responder group; Table 1). No significant differences with regard to age and sex distribution were observed between both groups. The responder-group had a more favourable disease state, was more chemotherapy-naive, and showed a trend towards a shorter duration of disease. In the responder-group, hypogammaglobulinaemia was not observed and gammaglobulin concentration was significantly higher. Total IgG-levels were significantly higher compared to the non-responder-group. Adequate response to vaccination was seen only in patients with total IgG levels within the normal range. Not all patients with normal gammaglobulin concentration and IgG-levels, however, showed an adequate response to vaccination; still seven (39%) of 18 patients with normal gammaglobulin concentrations and 5 (36%) of 14 patients with normal IgG-levels had a poor response to vaccination (data not shown). Significantly higher IgG2 and IgG4 concentrations were found in responders, whereas no differences

Table 1 Comparison of clinical and laboratory data (means 9 SD) of patients with adequate specific antibody responses to Pneumovax or Act-Hib and patients without responses to these vaccines Pneumovax

Mean age (range in years) Rai classificationh Rai 0 Rai 1 Rai 2 Rai 4 Duration B-CLL (range in months) Prior chemotherapy, no.of patients Hypogammaglobulinaemiaf Gammaglobulina Total IgMd Total IgGb IgG1 IgG2 IgG3 IgG4 Total IgAc SCD23 (Range in IU/ml) a

Act-Hib

Responder group (n = 5)

Non-responder group (n = 16)

Responder group (n =6)

Non-responder group (n =17)

729 5 (62–76) 4 0 1 0 36 916 (12–52) 0 0 12.692.47g 0.59 0.21f 9.79 1.4f 7.49 2.2 3.09 0.7e 0.59 0.2 0.49 0.2e 2.39 1.2h 45916e (15–58)

70 9 8 (49–85) 3 5 5 3 60 965 (6–240) 6 5 7.7 92.8i 0.3 90.1 6.3 92.6i 5.3 9 2.3i 1.8 91.2i 0.4 90.2i 0.1 90.2i 0.8 90.7 182 9120 (29–416)

69 910 (51–76) 5 1 0 0 36 9 19 (10–55) 0 0 11.7 91.6 f 0.5 90.1g 9.5 91.7f 7.2 92.5e 3.2 90.8e 0.5 90.3e 0.5 90.2h 2.1 91.2g 40 9 19g (15–67)

70 98 (49–85) 4 4 6 3 58 9 63 (9–240) 6 5 8.0 93.2 0.3 9 0.2 6.6 92.6 5.1 9 2.1 1.9 91.2 0.3 90.2 0.1 90.1 0.8 90.7 184 9115 (30–416)

Gammaglobulin and immunoglobulin concentration in g/l. Normal range 7.0–15.0 g/l. c Normal range 0.5–4.0 g/l. d Normal range 0.4–2.3 g/l. e PB0.05. f PB0.01. g PB0.005. h PB0.001 (all Student’s t-test, except for Rai classification; Wilcoxon rank test). i Mean gammaglobulin and IgG levels of 15 non-responder patients. One patient was omitted because of paraproteinemia in the IgG class. b

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Table 2 Relation between tetanus toxoid vaccination and antibody response to tetanus toxoid (TT) and H.influenzae type b capsular polysaccharide (Hib)a Act-Hib vaccination response

TT vaccination history

a

Prior vaccination n= 11 No prior vaccination n= 12

Act-Hib non-responder (n =17)

Act-Hib responder (n =6)

TT responder

TT non responder

TT responder

2 0

4 11

4 0

TT non responder 1 1

Total number of patients are given.

were found in IgG1 and IgG3 levels between both groups (Table 1). In all patients, soluble CD23 levels were measured. Soluble CD23 levels were significantly lower in patients with adequate specific antibody responses to Pneumovax® compared to the non-responder group (Table 1). Furthermore, a remarkably wide range in sCD23 levels was observed in the group of 9 patients with pre-vaccination antibody levels in the protective range. In four of those nine patients, vaccination with Pneumovax® did not result in a further increase in antibody titers. These four patients had higher sCD23-levels (\ 275 IU/ml) than the other five patients (data not shown).

3.2. Antibody response to conjugated Haemophilus influenzae type b-6accine One patient was excluded from analysis because of intercurrent therapy with gammaglobulin and one patient did not receive Act-Hib® vaccine. Twenty-three patients were, therefore, analysed with regard to their specific antibody responses to Act-Hib®. Prior to vaccination, specific antibody titres in the protective range against H. influenzae type b were present in eight (35%) of the 23 patients; three of these eight patients had adequate responses to vaccination. Low pre-vaccination specific antibody titres were found in 15 patients. Only three (20%) of these 15 patients responded to Act-Hib® vaccination. Following vaccination with Act-Hib®, the percentage of patients with sufficient antibody titers against H. influenzae type b increased from 35% (eight of 23 patients) to 48% (11 of 23 patients). Act-Hib® responder patients showed similar clinical and laboratory characteristics as Pneumovax-23® responder patients (Table 1).

3.3. Antibody response to the tetanus toxoid component of Act-Hib ® Specific antibody responses against tetanus toxoid were measured in 23 patients and were correlated to prior tetanus toxoid vaccination status and to specific anti-polysaccharide antibody responses on Act-Hib®. Eleven of 23 patients were immunised with tetanus

toxoid in the past (Table 2). In these patients a booster effect of the tetanus component of the Act-Hib vaccine could be expected; 6 (55%) of these 11 patients showed a specific anti-tetanus toxoid IgG antibody response to Act-Hib® vaccination. Four of these six patients also responded to the capsular polysaccharide component of H. influenzae type b of the Act-Hib® vaccine. Twelve patients reported a negative tetanus toxoid vaccination history. None of these patients gained adequate antibody responses to tetanus toxoid: one patient responded to H. influenzae type b (Table 2). Thus, prior tetanus toxoid vaccination leads to a significant (PB 0.05; Fisher’s exact test) better IgG anti-Hib antibody response upon vaccination with the Act-Hib® vaccine.

3.4. Antibody response to both pneumococcal polysaccharide 6accine and conjugated Haemophilus influenzae type b 6accine Two patients responded to Pneumovax® only (Table 3). Thus, these patients were capable of a T-cell independent antibody response to polysaccharide antigens of pneumococci, but not of Hib. Another three patients responded to both vaccines, but reacted heterogeneously to the tetanus-toxoid component of the Act-Hib® vaccine (Table 3). Two of these three patients had received tetanus-toxoid vaccination in the past; one patient showed a clear response and one patient did not. Thus, at least one patient was capable of T-cell independent as well as T-cell dependent antibody responses. The third patient without a tetanus-toxoid vaccination history responded to the capsular polysaccharide of Haemophilus influenzae type b; an anti-tetanus toxoid IgG antibody response was not observed. Therefore, in this patient the antibody response to the polysaccharide components in both vaccins seems to be T-cell independent. The two patients, who responded to the Act-Hib® vaccine only, had been vaccinated with tetanus-toxoid in the past and showed a response to the tetanus-toxoid booster as well (Table 3). These results are compatible with a T-cell dependent anti-polysaccharide antibody response.

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The response rate on Pneumovax® and Act-Hib® immunisation in our study is very poor when compared to vaccination responses obtained in immunocompetent individuals. Antibody responses were measured in serum samples obtained 3 weeks after vaccination. We can not exclude that in patients with a low response the antibody response also is slower and that higher antibody titres would have been reached later. A poor antibody response was also found by Mellemgaard et al., who performed a vaccination study in 40 patients with less advanced stages of B-CLL (primarily Binet stage A) with pneumococcal polysaccharide vaccine (Pneumovax®) [23]. Jurlander et al. found antibody response rates on Act-Hib® vaccination in four (29%) out of 14 patients with B-CLL: after boostervaccination the protection rate increased to 6 (43%) out of 14 patients [25]. However, in the same study response rates of 90% were found in 12 patients randomised to receive H2-receptor blockade. Previous reports showed higher immunogenicity for conjugated H. influenzae type b vaccines compared to purified capsular polysaccharide vaccines. Individuals who have been immunised with the carrier protein of conjugate vaccines can be expected to reach higher post-immunisation anti-polysaccharide antibody titres. No clear differences were found in our study in response rates to Pneumovax® and Act-Hib®; specific antibody responses to pneumococcal capsular polysaccharides did occur without concomitant response to Act-Hib® vaccination. This could be due to the absence of prior contact with the carrierprotein, i.c. tetanus-toxoid (TT). Indeed, we found that four out of six patients with prior TT-vaccination showing a positive anti-tetanus response now generated an anti-polysaccharide response upon conjugate vaccination. This finding is in accordance with previous observations [11,12]. On the contrary, five patients who were immunised with tetanus toxoid in the past did not respond to the carrier-protein and to the Hib polysaccharide. Improvement of specific antibody responses to vaccination with T-cell dependent antigens as tetanus toxoid and conjugated H. influenzae type b with adjuvant H2-receptor blockade is of particular interest for the non-responders. Although deterioration of T-cell function has been observed in B-CLL [27] and can not be excluded as a cause of impaired antibody response

3.5. Ad6erse reactions Patients were asked to fill out a questionnaire with respect to local symptoms at the site of inoculation and systemic symptoms (fever and changes in physical condition) possibly related to the vaccinations during the first 72 h after vaccination. In general, both vaccines were well tolerated. Major local or systemic reactions or deterioration of leukaemic disease were not observed.

4. Discussion Previous studies in patients with solid tumours and lymphoreticular neoplasms have lead to conflicting results with respect to the capacity to mount relevant antibody responses on vaccination with pneumococcal polysaccharide and conjugated H. influenzae type b vaccine. In immunocompetent individuals, seroconversion rates of 80% or more were obtained for Act-Hib® vaccination and for the pneumococcal serotypes responsible of bacteraemia, but response rates vary greatly with age [20,22]. In immunocompromised patients lower seroconversion rates are found [10,11] and protective efficacy of pneumococcal polysaccharide vaccination has been reported to be as low as 21% [7]. Thus far, only few studies have dealt with antibody responses to vaccination in patients with B-CLL in particular [23 –25]. We studied antibody responses to Pneumovax® and Act-Hib® because these vaccines are recommended in the elderly and in individuals with high risk of infections with encapsulated bacteria, as is the case in BCLL [20 –22,26]. Furthermore, these vaccines differ in the way they induce a humoral immune response. Purified polysaccharide antigens, as contained in the Pneumovax® vaccine, result in T-cell independent type2 antibody formation. In Act-Hib®, the polysaccharide antigen is conjugated to tetanus toxoid as a carrierprotein. As a result, antibody responses to the polysaccharide antigens of Hib can also be induced in a T-cell dependent way. T-cell dependent antigens induce immunological memory, resulting in the possibility of booster vaccinations. Table 3 Responders to Pneumovax-23 versus responders to Act-Hib Tetanus vaccination history

Act-Hib responder TT

Pneumovax responder Pneumovax non-responder Total

2 2

3 2 5

Act-Hib non-responder No TT

TT

1 0

1 5

Total No TT

2 13 15

1 8

5 15 20

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to a conjugated vaccine, it is questionable whether the intrinsic incapability of B-cells to mount a specific antibody response can be overcome by T-cell stimulation. Adequate antibody response to both vaccines was correlated with lower levels of soluble CD23 (sCD23). High levels of sCD23 have been found in B-CLL and have been correlated with more advanced stages of B-CLL. Rapid increase in sCD23 levels during the course of B-CLL has been associated with a poor prognostic outcome [13]. sCD23, a splitproduct of membrane-bound CD23, appears to act as a multifunctional cytokine and has biological activity of its own. sCD23 is involved in several aspects of B-cell activation and proliferation [28] and has a synergistic effect on histamine release [29]. Histamine acts as a mediator of immune and inflammatory reactions [30] and has a direct inhibitory effect on immunoglobulin production of B-cells in vitro [31]. Thus, it may be that a high sCD23 level in non-responders is not only a reflection of leukemic stage, but may also interfere with specific antibody response to vaccination. Four patients had high pre-vaccination titres against the S. pneumoniae capsular polysaccharides but did not respond to vaccination. Interestingly, these four patients all had high serum levels of sCD23. As sCD23 levels correlate positively with the lymphocyte doubling time in B-CLL patients, this might imply that these four patients have progressive disease at the time of vaccination with deterioration of B-cell function, which accordingly to the high pre-vaccination titres has recently begun. Not unexpectedly, specific antibody responses on vaccination were significantly correlated with less advanced disease state, absence of prior chemotherapy, normal gammaglobulin and immunoglobulin levels and higher total IgG-levels and IgG2 and IgG4 levels. Correlations between hypogammaglobulinaemia or decreased immunoglobulin levels and increased risk of infection [5,32] and inability to produce circulating antibodies on antigenic stimulation [3,24,33] have previously been reported. Deficiency of type specific antibody is by far the most identified immunological deficiency predisposing to pneumococcal infection [20]. Griffiths et al. reported a significant correlation between low titres of anti-pneumococcal antibodies with recurrent and/or serious infections in patients with BCLL [5]. In our study, we found higher IgG2 and IgG4 levels in patients with adequate antibody responses, as has been found in previous reports. [22,34 – 36]. Siber et al. demonstrated a clear correlation between the serum concentration of IgG2 and the ability to produce antibodies to S. pneumoniae and Haemophilus type b capsular polysaccharide antigens [34]. Futhermore, IgG2 and IgG4 subclass deficiency might contribute to infection with encapsulated bacteria [37]. In conclusion, specific antibody responses to vaccination in patients with B-

CLL are poor with respect to T-cell dependent as well as T-cell independent antigens. A positive response to pneumococcal polysaccharide vaccine and tetanus-toxoid conjugated H. influenzae type b vaccine are significantly correlated with less advanced disease stage and absence of hypogammaglobulinaemia. Furthermore, adequate antibody response to vaccination in patients with B-CLL is significantly correlated with higher levels of total IgG, IgG2 and IgG4 subclasses and lower levels of soluble CD23. Since the protection rate on vaccination is low, especially in advanced disease, these patients should be vaccinated as early as possible in the course of the disease, as soon as the diagnosis of B-CLL is made and post-vaccination specific antibody levels should be measured. Improvement of antibody responses in patients with B-CLL with more immunogenic vaccines, as conjugated pneumococcal or H. influenzae b polysaccharide vaccines, in combination with adjuvant H2-receptor blockade is encouraging, but needs confirmation.

Acknowledgements We thank Dr G. Veth, Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, for her assistance in this study.

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