Vaccine 33 (2015) 1688–1694
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Vaccination status and immune response to 13-valent pneumococcal conjugate vaccine in asplenic individuals Per Nived a,∗ , Charlotte Sværke Jørgensen b , Bo Settergren a a b
Department of Infectious Diseases, Central Hospital, Kristianstad, Sweden Department of Microbiological Diagnostics & Virology, Statens Serum Institut, Copenhagen, Denmark
a r t i c l e
i n f o
Article history: Received 1 December 2014 Received in revised form 1 February 2015 Accepted 11 February 2015 Available online 21 February 2015 Keywords: Pneumococcal vaccination Asplenia
a b s t r a c t Overwhelming post-splenectomy infection (OPSI) is immediately life-threatening and vaccination against encapsulated bacteria, in particular pneumococci, decreases its incidence. First, we investigated the adherence to vaccination guidelines in a retrospective study of the hospital records of splenectomised patients. Second, patients were asked to complete a questionnaire and invited to participate in a study where 12-valent pneumococcal serotype-specific IgG concentrations were determined before and 4 to 6 weeks after vaccination with PCV13. Of 79 individuals who underwent splenectomy between 2000 and 2012: 81.0% received pneumococcal vaccine, 51.9% received vaccine against Haemophilus influenzae type B and 22.8% received meningococcal vaccine. 31 individuals were deceased. 33 individuals completed questionnaires and accepted participation in the second part of the study. The participants consisted of two groups: (1) prior PPV23 (n = 24) and (2) prior PPV23 + PCV13 (n = 9). In group 1, pre-PCV13 GMC’s ≥ 0.35 g/mL were observed for serotypes 1, 4, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, and GMC’s < 0.35 g/mL for serotypes 3 and 5, significant increases pre- to post-PCV13 were found for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 23F (p ≤ 0.001) and 19F (p = 0.01) and all 12 serotypes-specific GMC were above 0.35 g/mL after vaccination. Group 2 did not receive vaccine in this study, but blood tests showed all 12 serotype-specific GMC > 0.35 g/mL. Adherence to guidelines regarding primary pneumococcal vaccination was adequate but only a minority received the recommended meningococcal vaccination. High levels of pneumococcal serotype-specific antibodies were observed in the previous PPV23 vaccinated group, and more pronounced in the previous PCV13 group, and our data suggests that PCV13 is immunogenic for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 19F and 23F, if used as a booster dose in asplenic patients with previous PPV23 vaccination. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction Patients who are asplenic or hyposplenic have a greatly increased risk of severe infections with encapsulated bacteria, in particular pneumococci. Overwhelming post-splenectomy infection (OPSI) is a serious disease that can progress to fulminant sepsis and death within less than 24 h [1]. The mortality in OPSI is 50–80% despite antibiotic and intensive care treatment [2]. Pneumococci are responsible for more than 50% of the cases of OPSI [3]. After the introduction of vaccination against encapsulated bacteria in connection with splenectomy, the incidence of OPSI has decreased [4].
∗ Corresponding author. Tel.: +46 443091550. E-mail address: [email protected] (P. Nived). http://dx.doi.org/10.1016/j.vaccine.2015.02.026 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
In the United States, guidelines from the Centers for Disease Control and Prevention (CDC), published in 1997 and updated in 2010, recommended the use of the 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults with anatomical or functional asplenia and revaccination after 5 years [5]. Whether patients should be recommended pneumococcal polysaccharide vaccine (PPV) or pneumococcal conjugate vaccine (PCV) and the possible benefits of repeated vaccinations is the subject of a current debate [6–8]. Heidelberger et al. demonstrated weaker antibody responses to a second immunization with capsular polysaccharides [9]; however, there has been concern that sensitization may induce immune tolerance [10]. While PPV induces a T-cell independent immune response, the conjugation of a protein to the pneumococcal polysaccharide leads to a T-cell dependent immune response and an immunological memory. In 2012, CDC published new guidelines for the use of PCV13 and PPV23 for adults with
P. Nived et al. / Vaccine 33 (2015) 1688–1694
immunocompromising conditions [11]. Asplenic or immunocompromised persons who are pneumococcal vaccine-naïve should receive one dose of PCV13 followed after at least eight weeks by one dose of PPV23, and persons who have previously received ≥1 dose of PPV23 should be given a PCV13 dose ≥1 year after the last PPV23 dose was received. Furthermore, a second dose of PPV23 should be given at least five years after the first PPV23 dose and no sooner than 8 weeks after PCV13. Since 1994, the Swedish National Board of Health and Welfare has recommended PPV23 to defined risk groups, including patients with anatomical or functional asplenia [12]. A booster dose is recommended to adults 5 to 10 years after the primary vaccination. The pneumococcal conjugate vaccine was introduced in the Swedish child immunization schedule in 2009 but there are still no official recommendations for the use of PCV in asplenic adults. PPV23 has been shown to reduce the incidence of invasive pneumococcal disease (IPD) by 50–70% [8]. The immune response to PPV23 is adequate in asplenic patients but suboptimal in patients with immune deficiencies [13,14]. PCV has a protective effect of 90% against invasive pneumococcal disease and the 7-valent pneumococcal conjugate vaccine (PCV7) has a documented adequate immune response in asplenic children [15]. In a study of 111 asplenic adults (median age 54.8 years) who received PCV7, significant increases in serotype-specific IgG geometric mean concentrations were observed pre- to post-PCV7 for the PCV7 serotypes, though concentrations ≥0.35 g/mL were demonstrated pre-PCV7 in a majority of participants due to prior PPV23 vaccination [16]. Results from this study further showed that, following PCV7, the percentage of asplenic individuals with serotype-specific IgG concentrations ≥1.00 g/mL increased significantly for serotypes 4, 6B, 9V, 19F, and 23F. PCV13 is identical in formulation for the seven common serotypes in PCV7 (4, 6B, 9V, 14, 18C, 19F, and 23F), but contains six additional antigens: 1, 3, 5, 6A, 19A, and 7F. The aims of this study were to investigate the adherence to vaccination guidelines as outlined above and to investigate the immunogenicity to PCV13 in splenectomised individuals.
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2.2. Blood specimens and antibody assays For all participants, blood samples were collected at the time of inclusion in the study (up to two months before vaccination). The subgroup of patients who received PCV13 in this study were instructed to return for a second set of blood samples four to six weeks after vaccination. Sera (0.5 mL) were frozen at −20 ◦ C and subsequently analysed at Statens Serum Institut, Copenhagen, Denmark. Pneumococcal serotype-specific IgG concentrations were determined for twelve serotypes (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) included in both PPV23 and PCV13, using a luminex method based on the procedure described by Lal et al. [17]. 2.3. Vaccination All participants who had neither received PCV13 previously nor PPV23 within the last year, and without contraindications, were vaccinated with one dose PCV13 (Prevenar 13® , Pfizer). Participants with a PPV23 vaccination within the last year also received a dose of PCV13 if ≥2 pneumococcal serotype-specific IgG concentrations were below 0.35 g/mL. PCV13 was administered as an intramuscular injection in the deltoid muscle. 2.4. Statistical analysis The age and sex of participants vs non-participants were compared using the Chi square test. Pneumococcal serotype-specific IgG concentrations were expressed as geometric mean concentrations (GMC) with 95% confidence intervals (CI). IgG concentrations pre- and post-PCV13 were log transformed and significance of changes were analysed using paired T-test. Subgroup analyses were performed using the Wilcoxon matched-pairs signed-rank test. Proportions of subjects with serotype-specific IgG concentrations ≥0.35, 1.00 and 5.00 g/mL were calculated and the significance of changes pre- to post-PCV13 were tested for each serotype using an exact McNemar’s test. Statistical analyses were made using Microsoft Excel 2010 and Stata® 12.0. 3. Results
2. Materials and methods 2.1. Study population and data collection
3.1. Demographics, diagnoses and vaccine coverage of the splenectomy cohort
All patients who underwent splenectomy at the Central Hospital Kristianstad, Sweden, during the period January 2000 to October 2012 were identified through the surgical planning database (Orbit), using ICD-10 procedure codes for splenectomy (JMA00) and abdominal splenectomy (JMA10). Further, the date of splenectomy and the underlying diagnosis leading to splenectomy were identified. All patients received an invitation letter and were asked to complete a questionnaire regarding relevant prior vaccinations, the reason for splenectomy, possible current medications or chronic illnesses affecting the immune system. Additional information regarding the above questions was obtained from the patients’ clinical records. Patients were offered individual appointments for information about the study. All patients able to give written, informed consents were eligible for inclusion in the study. Participants completed all study visits at the Department of Infectious Diseases, Central Hospital Kristianstad, Sweden. All data were anonymised and stored in a Microsoft Excel file. The study was approved by the regional ethics committee at Lund University, Sweden (Dnr 2013/204).
A total of 78 patients were splenectomised at the Central Hospital Kristianstad between January 2000 and October 2012. At the time of splenectomy, the median age was 61.5 years (range 11–88 years). Thirty-one of the splenectomised individuals were deceased at the start of this study. Five patients (6.4%) had died within 14 days post-splenectomy. Twelve patients had died at the hospital, and the following causes of death were identified in records: pneumonia or sepsis of unknown etiology (n = 4), terminal cancer (n = 3), haemorrhage (n = 2), pneumonia and septic shock caused by non-typeable Haemophilus influenzae (n = 1), multitrauma (n = 1), and cardiac failure (n = 1). Nineteen patients had died in a hospice, nursing home or at home, and the final causes of death in this group is unknown to the authors but ten of the patients had been diagnosed with metastatic cancer. Regarding vaccination against pneumococci, 64 individuals (81.0%) had received at least one dose of PPV23 and 11 (13.9%) had been vaccinated with PCV13. Five patients had received PCV13 as a primary vaccine followed by PPV23 after 8 weeks. Twenty (64.5%) of the deceased patients had received at least one dose of PPV23 and none had received PCV13. Pneumococcal vaccination had been repeated with PPV23 and PCV13 in 17.7% and 7.7%, respectively of
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Table 1 Splenectomy cohort demographics, diagnoses and relevant vaccinations before this study.
Men, number (%) Median age in years (range) at time of splenectomy Reason for splenectomy, number (%) Solid organ malignancy Hematological malignancy Abdominal surgery due to benign process Trauma Non-neoplastic hematological disease Previous vaccination, number (%) PPV23, 1 dose PPV23, ≥2 doses PCV13 Hib Meningococcal Unknown vaccination status
All study patients (n = 79)
Deceased (n = 31)
Living (n = 48)
40 (50.6) 61 (11–88)
18 (58.1) 77 (31–88)
22 (45.8) 46 (11–80)
22 (27.8) 9 (11.4) 23 (29.1) 18 (22.8) 7 (8.9)
17 (54.8) 3 (9.7) 6 (19.4) 3 (9.7) 2 (6.5)
5 (10.4) 6 (12.5) 17 (35.4) 15 (31.3) 5 (10.4)
50 (63.3) 14 (17.7) 11 (13.9) 41 (51.9) 18 (22.8) 9 (11.4)
20 (64.5) 0 0 11 (35.5) 2 (6.5) 6 (19.4)
30 (62.5) 14 (29.2) 11 (22.9) 30 (62.5) 16 (33.3) 3 (6.3)
Table 2 Study population demographics and reasons for splenectomy.
Men, number (%) Mean age in years (range) at time of study Reason for splenectomy, number (%) Solid organ malignancy Hematological malignancy Abdominal surgery due to benign process Trauma Non-neoplastic hematological disease Previous vaccination, number (%) PPV23, 1 dose PPV23, ≥2 doses PCV13 Hib Meningococcal vaccine
Fig. 1. Organizational chart of the splenectomy cohort, the pneumococcal serology study population and subgroups.
the 60 individuals (76.9%) who had been splenectomised more than 5 years prior to the study, 23 (38.3%) had died within 5 years postsplenectomy. Ideally, the remaining 37 individuals should all have received a second dose pneumococcal vaccine after 5 years but our data suggest that only 19 (51.4%) received one or more follow up doses of either PPV23 or PCV13. The number of patients vaccinated against Hib and meningococci were 41 (51.9%) and 18 (22.8%), respectively. For nine patients (11.5%) data was missing. For the splenectomy cohort, demographics, reason for splenectomy and relevant vaccinations are summarized in Table 1. 3.2. Pneumococcal serology study population Among the 48 surviving individuals in the splenectomy cohort, we received informed consent from 33 individuals, all of whom were included in the pneumococcal serology study (Fig. 1). The
Participants (n = 33)
Nonparticipants (n = 15)
14 (42.4) 52 (22–80)
8 (53.3) 61 (25–87)
4 (12.1) 5 (15.2) 9 (27.3)
2 (13.3) 2 (13.3) 6 (40.0)
11 (33.3) 4 (12.1)
5 (33.3) 0
19 (57.6) 13 (39.4) 9 (27.3) 21 (63.6) 12 (36.4)
12 (80.0) 1 (6.7) 2 (13.3) 9 (60.0) 4 (26.7)
main reasons for splenectomy among the included patients were trauma in 11 cases (33.3%) and abdominal surgery due to a benign process in 9 cases (27.3%). The non-participant group showed a similar pattern. Demographics and underlying reasons for splenectomy in participants and non-participants are shown in Table 2. There were no significant differences in the age and sex distribution in the participant group compared to the non-participants. The following primary pneumococcal vaccination data were found in the patient records: 28 individuals had received a dose of PPV23, and 4 individuals had received a dose of PCV13 followed after eight weeks by a dose of PPV23. Twelve individuals reported having received two doses of PPV23, and of these 11 could be confirmed by cross-checking in patient records. One individual had been vaccinated with 3 PPV23 doses (confirmed in the patient record). Five individuals received one dose of PCV13 as revaccination after PPV23, according to patient records. Thus, 24 individuals were PCV13 naïve and 9 individuals had previously received PCV13 vaccination. 3.3. Previous PCV13 group A subgroup of 9 individuals with previous PCV13 vaccination did not receive PCV13 in this study, but a single set of blood samples were collected to determine the pneumococcal serotype-specific IgG concentrations. All individuals in this group were immunocompetent. All 12 serotype-specific GMC’s were above 0.35 g/mL and 89–100% of individuals had antibody levels above this threshold, except for serotypes 3 and 5.
*
**
Subgroup immunocompetent. Subgroup immunocompromised.
1.27 (0.1–10.9) 3.00 (0.7–13.0) 2.67 (0.9–7.6) 0.19 (0.0–0.8) 0.29 (0.1–0.9) 0.24 (0.1–0.9) 1.50 (0.5–4.7) 0.90 (0.2–4.1) 1.90 (0.7–5.0) 1.13 (0.2–6.3) 0.47 (0.1–2.0) 2.89 (1.0–8.4) 2.14 (0.6–7.4) 4.17 (1.3–13.7) 0.36 (0.1–1.4) 0.67 (0.1–3.2) 1.14 (0.1–12.7) 0.81 (0.1–6.3) 1.06 (0.1–7.8) 1.30 (0.4–4.4) 0.91 (0.1–10.4) 0.76 (0.1–4.6) 4.10 (1.0–17.2) 1.53 (0.4–6.6) 8 7
2.07 (1.4–3.1) 1.69 (1.0–2.9) 2.14 (1.6–2.9) 6.21 (2.9–13.1) 0.71 (0.4–1.4) 5.60 3.6–8.6) 3.57 (2.2–5.9) 2.68 (1.8–4.0) 1.70 (0.8–3.5) 4.60 (2.5–8.4) 2.68 (1.7–4.1) 8.39 3.0–23.2) 2.07 (1.0–4.3) 9.19 (5.5–15.4) 5.96 (3.4–10.5) 8.62 (5.1–14.5) 5.54 (3.0–10.2) 0.28 (0.1–0.5) 0.51 (0.3–0.9) 0.24 (0.1–0.5) 9.29 (5.5–15.6) 0.53 (0.3–0.9) 1.48 (0.7–3.1) 1.10 (0.3–4.0) 15 14
19F 19A 18C 14 9V 7F
1.85 (1.2–2.8) 1.35 (0.8–2.4) 2.06 (1.5–2.9) 3.44 (1.6–7.4) 0.62 (0.3–1.1) 4.45 (2.9–6.9) 2.99 (1.8–4.9) 1.33 (0.6–2.8) 2.82 (1.4–5.9) 2.11 (1.3–3.3) 3.99 (1.4–11.4) 1.49 (0.7–3.0) 7.02 (4.1–12.0) 3.79 (2.1–7.0)
6B 5 4 3
4.30 (2.6–7.2) 0.24 (0.1–0.4) 0.42 (0.3–0.7) 0.24 (0.1–0.4) 7.11 (4.3–11.6) 0.47 (0.3–0.8) 1.14 (0.6–2.2) 1.12 (0.4–3.2)
1
PCV13 serotypes
N GMC, g/mL (95% CI)
Table 3 Geometric mean concentrations (GMC) before and after PCV13 vaccination.
Twenty-four individuals had not previously received PCV13. In this group, the following numbers of individuals (%, range of time since the last dose of PPV23) had received 1, 2 and 3 doses of PPV23, respectively: 12 (50.0%, 0.8–13.0 years), 10 (41.7%, 0.5–6.5 years) and 1 (4.2%, 1.3 years). Mean years since vaccination were 4.6 (0.5–13.0 years). Nine individuals were considered to be immunocompromised for the following reasons: haematological malignancies (n = 5), ongoing immunosuppressive treatment (n = 3, methotrexate or rituximab) and generalized solid organ malignancy (n = 1). All individuals in this group were vaccinated with a dose of PCV13. Two individuals had been vaccinated with a dose of PPV23 within a year of this study but fulfilled our criteria for PCV13 vaccination after receiving the results of the pneumococcal serology analyses (≥2 pneumococcal serotype-specific antibodies 200 cells/L, from the United States and Europe, where the antibody response to a single dose of PCV7 was comparable with PPV23 for the serotypes evaluated [20–23]. Serotypes 1 and 19A had the highest observed pre-PCV13 titres (GMCs > 4 g/mL), but were less prevalent in the population of Scania, Sweden, compared to serotypes 7F, 14, 3, 4, 9V, 23F, and 6B, and only represented 3.4% and 3.7%, respectively, of 436 pneumococcal blood isolates from this population during 2009–2010 [Personal communication]. We observed significant increases in pre- to post-PCV13 pairs of antibody concentrations for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 19F and 23F, and for serotypes 9V and 14 tendencies toward increase were found. In contrast, a slight decrease in post-PCV13 concentrations for serotype 6B was observed. Notably, a dose of PCV13 contains the double amount of serotype 6B (4.4 g/dose) compared to the other serotypes (2.2 g/dose). However, it is possible that an equal or higher response to serotype 6B could be found if the quality of antibodies, e.g. avidity or opsonophagocytic activity (OPA), was measured. In a subgroup analysis of immunocompromised patients, significant increases were found for serotypes 4, 18C, and 23F pre- to post-PCV13 but the number of patients is too small for making any reliable conclusions. Previous studies of asplenic individuals have demonstrated good immunological responses to PCV7. Stanford et al. studied 111 splenectomised individuals, of whom 97% had previously received PPV23 and 70% had received a PPV23 dose within 5 years prior to the PCV7 vaccination study, and observed high serotype-specific IgG concentrations pre-PCV7, with significant increases (p < 0.01) in GMC’s pre- to post-PCV7 for the PCV7 serotypes [16]. MeerveldEggink et al. vaccinated 54 asplenic patients with two doses of PCV7 followed by PPV23 after six months; 76% had received PPV23 in the past, and the mean time since the last vaccination was 8.6 years [24]. They observed significant increases in serotype-specific IgG GMC’s after the first dose for all seven serotypes, no further increases after the second dose, except for serotype 4, and no significant increases were found after PPV23 [24]. Our study has some limitations. Adherence to vaccination guidelines was investigated retrospectively based on patient records, questionnaires and interviews of 69% of living patients. Primary vaccination data were easily found in hospital records, but the collection of revaccination data was based on patient statements.
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There are obvious limitations to this method, but we were able to crosscheck 92% of the statements regarding PPV23 booster doses. Fifteen individuals (31%) did not participate in the study. Due to small numbers of patients in the subgroups, our possibilities for conclusions were limited. The World Health Organisation (WHO) has recommended a protective threshold ≥0.35 g/mL of serotypespecific IgG following conjugate immunization in children [25], but the relevance of this threshold for protection against invasive pneumococcal disease (IPD) in adults is unclear. Pneumococcal antibody levels have been shown to increase with age and inversely the incidence of IPD decreases, except for the elderly; although the proportion of older people with antibody levels ≥0.35 g/mL remains high, the incidence of IPD is elevated compared to young adults [26]. Furthermore, serotype-specific IgG concentrations are not necessarily correlated with the immunity in vivo. It has been proposed that measuring antibody avidity and using functional antibody assays are more appropriate in elderly individuals [27]. Current US recommendations on the use of PCV13 in adults are based on two randomized multicentre studies, that used OPA to measure immunogenicity [11]. In conclusion, adherence to pneumococcal vaccination guidelines in the splenectomy cohort was adequate, at least in terms of primary vaccination. In contrast, vaccination against Neisseria meningitidis serogroups A + C was insufficient. There is a need to improve the awareness among healthcare professionals of the greatly increased risk of severe infection with encapsulated bacteria post-splenectomy and how these infections, in particular overwhelming post-splenectomy infection, can be prevented. In the second part of this study, high levels of serotype-specific IgG concentration ≥0.35 g/mL were observed in previous PPV23 vaccinated but PCV-naïve asplenic patients. Further our results suggest that PCV13 is immunogenic for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 19F, and 23F, if used as a booster dose in asplenic patients with previous PPV23 vaccination. Larger studies are needed to confirm our results, to better evaluate the immunological responses for serotypes 6A, 6B, 9V and 14, and to investigate the immunological and long-term protective effects of PCV13 used as a primary pneumococcal vaccination in asplenic patients. Role of the funding source This work was supported by an unrestricted grant from the Research and Development Committee (FoU-kommittén) at the Central Hospital Kristianstad, Sweden. Conflict of interest statement None of the authors has any conflict of interest relevant to this article to declare. Acknowledgements The authors would like to thank Åsa Möllerstedt at the Clinic for Infectious Diseases for her invaluable help with patient contacts and blood sampling, and Inger Nilsson at the Department for Clinical Chemistry for preparing samples for serology testing. References [1] Werner S, Winstedt D, Kander T. [29-year-old man treated with splenectomy died of pneumococcal sepsis. Important that pneumococcal vaccination of splenectomised is not forgotten]. Lakartidningen 2012;109:1404–5. [2] Holdsworth RJ, Irving AD, Cuschieri A. Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br J Surg 1991;78:1031–8. [3] Davidson RN, Wall RA. Prevention and management of infections in patients without a spleen. Clin Microbiol Infect 2001;7:657–60.
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[25] World Health Organization. Recommendations for the production and control of pneumococcal conjugate vaccines. WHO Tech Rep Ser 2005;927(Annex2):64–98. [26] Balmer P, Borrow R, Findlow J, Warrington R, Frankland S, Waight P, et al. Agestratified prevalences of pneumococcal-serotype-specific immunoglobulin G in England and their relationship to the serotype-specific incidence of invasive pneumococcal disease prior to the introduction of the
pneumococcal 7-valent conjugate vaccine. Clin Vaccine Immunol 2007;14:1442–50, http://dx.doi.org/10.1128/CVI. 00264-07. [27] Romero-Steiner S, Musher DM, Cetron MS, Pais LB, Groover JE, Fiore AE, et al. Reduction in functional antibody activity against Streptococcus pneumoniae in vaccinated elderly individuals highly correlates with decreased IgG antibody avidity. Clin Infect Dis 1999;29:281–8, http://dx.doi.org/10.1086/520200.
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Vaccination status and immune response to 13-valent pneumococcal conjugate vaccine in asplenic individuals Per Nived a,∗ , Charlotte Sværke Jørgensen b , Bo Settergren a a b
Department of Infectious Diseases, Central Hospital, Kristianstad, Sweden Department of Microbiological Diagnostics & Virology, Statens Serum Institut, Copenhagen, Denmark
a r t i c l e
i n f o
Article history: Received 1 December 2014 Received in revised form 1 February 2015 Accepted 11 February 2015 Available online 21 February 2015 Keywords: Pneumococcal vaccination Asplenia
a b s t r a c t Overwhelming post-splenectomy infection (OPSI) is immediately life-threatening and vaccination against encapsulated bacteria, in particular pneumococci, decreases its incidence. First, we investigated the adherence to vaccination guidelines in a retrospective study of the hospital records of splenectomised patients. Second, patients were asked to complete a questionnaire and invited to participate in a study where 12-valent pneumococcal serotype-specific IgG concentrations were determined before and 4 to 6 weeks after vaccination with PCV13. Of 79 individuals who underwent splenectomy between 2000 and 2012: 81.0% received pneumococcal vaccine, 51.9% received vaccine against Haemophilus influenzae type B and 22.8% received meningococcal vaccine. 31 individuals were deceased. 33 individuals completed questionnaires and accepted participation in the second part of the study. The participants consisted of two groups: (1) prior PPV23 (n = 24) and (2) prior PPV23 + PCV13 (n = 9). In group 1, pre-PCV13 GMC’s ≥ 0.35 g/mL were observed for serotypes 1, 4, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, and GMC’s < 0.35 g/mL for serotypes 3 and 5, significant increases pre- to post-PCV13 were found for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 23F (p ≤ 0.001) and 19F (p = 0.01) and all 12 serotypes-specific GMC were above 0.35 g/mL after vaccination. Group 2 did not receive vaccine in this study, but blood tests showed all 12 serotype-specific GMC > 0.35 g/mL. Adherence to guidelines regarding primary pneumococcal vaccination was adequate but only a minority received the recommended meningococcal vaccination. High levels of pneumococcal serotype-specific antibodies were observed in the previous PPV23 vaccinated group, and more pronounced in the previous PCV13 group, and our data suggests that PCV13 is immunogenic for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 19F and 23F, if used as a booster dose in asplenic patients with previous PPV23 vaccination. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction Patients who are asplenic or hyposplenic have a greatly increased risk of severe infections with encapsulated bacteria, in particular pneumococci. Overwhelming post-splenectomy infection (OPSI) is a serious disease that can progress to fulminant sepsis and death within less than 24 h [1]. The mortality in OPSI is 50–80% despite antibiotic and intensive care treatment [2]. Pneumococci are responsible for more than 50% of the cases of OPSI [3]. After the introduction of vaccination against encapsulated bacteria in connection with splenectomy, the incidence of OPSI has decreased [4].
∗ Corresponding author. Tel.: +46 443091550. E-mail address: [email protected] (P. Nived). http://dx.doi.org/10.1016/j.vaccine.2015.02.026 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
In the United States, guidelines from the Centers for Disease Control and Prevention (CDC), published in 1997 and updated in 2010, recommended the use of the 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults with anatomical or functional asplenia and revaccination after 5 years [5]. Whether patients should be recommended pneumococcal polysaccharide vaccine (PPV) or pneumococcal conjugate vaccine (PCV) and the possible benefits of repeated vaccinations is the subject of a current debate [6–8]. Heidelberger et al. demonstrated weaker antibody responses to a second immunization with capsular polysaccharides [9]; however, there has been concern that sensitization may induce immune tolerance [10]. While PPV induces a T-cell independent immune response, the conjugation of a protein to the pneumococcal polysaccharide leads to a T-cell dependent immune response and an immunological memory. In 2012, CDC published new guidelines for the use of PCV13 and PPV23 for adults with
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immunocompromising conditions [11]. Asplenic or immunocompromised persons who are pneumococcal vaccine-naïve should receive one dose of PCV13 followed after at least eight weeks by one dose of PPV23, and persons who have previously received ≥1 dose of PPV23 should be given a PCV13 dose ≥1 year after the last PPV23 dose was received. Furthermore, a second dose of PPV23 should be given at least five years after the first PPV23 dose and no sooner than 8 weeks after PCV13. Since 1994, the Swedish National Board of Health and Welfare has recommended PPV23 to defined risk groups, including patients with anatomical or functional asplenia [12]. A booster dose is recommended to adults 5 to 10 years after the primary vaccination. The pneumococcal conjugate vaccine was introduced in the Swedish child immunization schedule in 2009 but there are still no official recommendations for the use of PCV in asplenic adults. PPV23 has been shown to reduce the incidence of invasive pneumococcal disease (IPD) by 50–70% [8]. The immune response to PPV23 is adequate in asplenic patients but suboptimal in patients with immune deficiencies [13,14]. PCV has a protective effect of 90% against invasive pneumococcal disease and the 7-valent pneumococcal conjugate vaccine (PCV7) has a documented adequate immune response in asplenic children [15]. In a study of 111 asplenic adults (median age 54.8 years) who received PCV7, significant increases in serotype-specific IgG geometric mean concentrations were observed pre- to post-PCV7 for the PCV7 serotypes, though concentrations ≥0.35 g/mL were demonstrated pre-PCV7 in a majority of participants due to prior PPV23 vaccination [16]. Results from this study further showed that, following PCV7, the percentage of asplenic individuals with serotype-specific IgG concentrations ≥1.00 g/mL increased significantly for serotypes 4, 6B, 9V, 19F, and 23F. PCV13 is identical in formulation for the seven common serotypes in PCV7 (4, 6B, 9V, 14, 18C, 19F, and 23F), but contains six additional antigens: 1, 3, 5, 6A, 19A, and 7F. The aims of this study were to investigate the adherence to vaccination guidelines as outlined above and to investigate the immunogenicity to PCV13 in splenectomised individuals.
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2.2. Blood specimens and antibody assays For all participants, blood samples were collected at the time of inclusion in the study (up to two months before vaccination). The subgroup of patients who received PCV13 in this study were instructed to return for a second set of blood samples four to six weeks after vaccination. Sera (0.5 mL) were frozen at −20 ◦ C and subsequently analysed at Statens Serum Institut, Copenhagen, Denmark. Pneumococcal serotype-specific IgG concentrations were determined for twelve serotypes (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) included in both PPV23 and PCV13, using a luminex method based on the procedure described by Lal et al. [17]. 2.3. Vaccination All participants who had neither received PCV13 previously nor PPV23 within the last year, and without contraindications, were vaccinated with one dose PCV13 (Prevenar 13® , Pfizer). Participants with a PPV23 vaccination within the last year also received a dose of PCV13 if ≥2 pneumococcal serotype-specific IgG concentrations were below 0.35 g/mL. PCV13 was administered as an intramuscular injection in the deltoid muscle. 2.4. Statistical analysis The age and sex of participants vs non-participants were compared using the Chi square test. Pneumococcal serotype-specific IgG concentrations were expressed as geometric mean concentrations (GMC) with 95% confidence intervals (CI). IgG concentrations pre- and post-PCV13 were log transformed and significance of changes were analysed using paired T-test. Subgroup analyses were performed using the Wilcoxon matched-pairs signed-rank test. Proportions of subjects with serotype-specific IgG concentrations ≥0.35, 1.00 and 5.00 g/mL were calculated and the significance of changes pre- to post-PCV13 were tested for each serotype using an exact McNemar’s test. Statistical analyses were made using Microsoft Excel 2010 and Stata® 12.0. 3. Results
2. Materials and methods 2.1. Study population and data collection
3.1. Demographics, diagnoses and vaccine coverage of the splenectomy cohort
All patients who underwent splenectomy at the Central Hospital Kristianstad, Sweden, during the period January 2000 to October 2012 were identified through the surgical planning database (Orbit), using ICD-10 procedure codes for splenectomy (JMA00) and abdominal splenectomy (JMA10). Further, the date of splenectomy and the underlying diagnosis leading to splenectomy were identified. All patients received an invitation letter and were asked to complete a questionnaire regarding relevant prior vaccinations, the reason for splenectomy, possible current medications or chronic illnesses affecting the immune system. Additional information regarding the above questions was obtained from the patients’ clinical records. Patients were offered individual appointments for information about the study. All patients able to give written, informed consents were eligible for inclusion in the study. Participants completed all study visits at the Department of Infectious Diseases, Central Hospital Kristianstad, Sweden. All data were anonymised and stored in a Microsoft Excel file. The study was approved by the regional ethics committee at Lund University, Sweden (Dnr 2013/204).
A total of 78 patients were splenectomised at the Central Hospital Kristianstad between January 2000 and October 2012. At the time of splenectomy, the median age was 61.5 years (range 11–88 years). Thirty-one of the splenectomised individuals were deceased at the start of this study. Five patients (6.4%) had died within 14 days post-splenectomy. Twelve patients had died at the hospital, and the following causes of death were identified in records: pneumonia or sepsis of unknown etiology (n = 4), terminal cancer (n = 3), haemorrhage (n = 2), pneumonia and septic shock caused by non-typeable Haemophilus influenzae (n = 1), multitrauma (n = 1), and cardiac failure (n = 1). Nineteen patients had died in a hospice, nursing home or at home, and the final causes of death in this group is unknown to the authors but ten of the patients had been diagnosed with metastatic cancer. Regarding vaccination against pneumococci, 64 individuals (81.0%) had received at least one dose of PPV23 and 11 (13.9%) had been vaccinated with PCV13. Five patients had received PCV13 as a primary vaccine followed by PPV23 after 8 weeks. Twenty (64.5%) of the deceased patients had received at least one dose of PPV23 and none had received PCV13. Pneumococcal vaccination had been repeated with PPV23 and PCV13 in 17.7% and 7.7%, respectively of
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Table 1 Splenectomy cohort demographics, diagnoses and relevant vaccinations before this study.
Men, number (%) Median age in years (range) at time of splenectomy Reason for splenectomy, number (%) Solid organ malignancy Hematological malignancy Abdominal surgery due to benign process Trauma Non-neoplastic hematological disease Previous vaccination, number (%) PPV23, 1 dose PPV23, ≥2 doses PCV13 Hib Meningococcal Unknown vaccination status
All study patients (n = 79)
Deceased (n = 31)
Living (n = 48)
40 (50.6) 61 (11–88)
18 (58.1) 77 (31–88)
22 (45.8) 46 (11–80)
22 (27.8) 9 (11.4) 23 (29.1) 18 (22.8) 7 (8.9)
17 (54.8) 3 (9.7) 6 (19.4) 3 (9.7) 2 (6.5)
5 (10.4) 6 (12.5) 17 (35.4) 15 (31.3) 5 (10.4)
50 (63.3) 14 (17.7) 11 (13.9) 41 (51.9) 18 (22.8) 9 (11.4)
20 (64.5) 0 0 11 (35.5) 2 (6.5) 6 (19.4)
30 (62.5) 14 (29.2) 11 (22.9) 30 (62.5) 16 (33.3) 3 (6.3)
Table 2 Study population demographics and reasons for splenectomy.
Men, number (%) Mean age in years (range) at time of study Reason for splenectomy, number (%) Solid organ malignancy Hematological malignancy Abdominal surgery due to benign process Trauma Non-neoplastic hematological disease Previous vaccination, number (%) PPV23, 1 dose PPV23, ≥2 doses PCV13 Hib Meningococcal vaccine
Fig. 1. Organizational chart of the splenectomy cohort, the pneumococcal serology study population and subgroups.
the 60 individuals (76.9%) who had been splenectomised more than 5 years prior to the study, 23 (38.3%) had died within 5 years postsplenectomy. Ideally, the remaining 37 individuals should all have received a second dose pneumococcal vaccine after 5 years but our data suggest that only 19 (51.4%) received one or more follow up doses of either PPV23 or PCV13. The number of patients vaccinated against Hib and meningococci were 41 (51.9%) and 18 (22.8%), respectively. For nine patients (11.5%) data was missing. For the splenectomy cohort, demographics, reason for splenectomy and relevant vaccinations are summarized in Table 1. 3.2. Pneumococcal serology study population Among the 48 surviving individuals in the splenectomy cohort, we received informed consent from 33 individuals, all of whom were included in the pneumococcal serology study (Fig. 1). The
Participants (n = 33)
Nonparticipants (n = 15)
14 (42.4) 52 (22–80)
8 (53.3) 61 (25–87)
4 (12.1) 5 (15.2) 9 (27.3)
2 (13.3) 2 (13.3) 6 (40.0)
11 (33.3) 4 (12.1)
5 (33.3) 0
19 (57.6) 13 (39.4) 9 (27.3) 21 (63.6) 12 (36.4)
12 (80.0) 1 (6.7) 2 (13.3) 9 (60.0) 4 (26.7)
main reasons for splenectomy among the included patients were trauma in 11 cases (33.3%) and abdominal surgery due to a benign process in 9 cases (27.3%). The non-participant group showed a similar pattern. Demographics and underlying reasons for splenectomy in participants and non-participants are shown in Table 2. There were no significant differences in the age and sex distribution in the participant group compared to the non-participants. The following primary pneumococcal vaccination data were found in the patient records: 28 individuals had received a dose of PPV23, and 4 individuals had received a dose of PCV13 followed after eight weeks by a dose of PPV23. Twelve individuals reported having received two doses of PPV23, and of these 11 could be confirmed by cross-checking in patient records. One individual had been vaccinated with 3 PPV23 doses (confirmed in the patient record). Five individuals received one dose of PCV13 as revaccination after PPV23, according to patient records. Thus, 24 individuals were PCV13 naïve and 9 individuals had previously received PCV13 vaccination. 3.3. Previous PCV13 group A subgroup of 9 individuals with previous PCV13 vaccination did not receive PCV13 in this study, but a single set of blood samples were collected to determine the pneumococcal serotype-specific IgG concentrations. All individuals in this group were immunocompetent. All 12 serotype-specific GMC’s were above 0.35 g/mL and 89–100% of individuals had antibody levels above this threshold, except for serotypes 3 and 5.
*
**
Subgroup immunocompetent. Subgroup immunocompromised.
1.27 (0.1–10.9) 3.00 (0.7–13.0) 2.67 (0.9–7.6) 0.19 (0.0–0.8) 0.29 (0.1–0.9) 0.24 (0.1–0.9) 1.50 (0.5–4.7) 0.90 (0.2–4.1) 1.90 (0.7–5.0) 1.13 (0.2–6.3) 0.47 (0.1–2.0) 2.89 (1.0–8.4) 2.14 (0.6–7.4) 4.17 (1.3–13.7) 0.36 (0.1–1.4) 0.67 (0.1–3.2) 1.14 (0.1–12.7) 0.81 (0.1–6.3) 1.06 (0.1–7.8) 1.30 (0.4–4.4) 0.91 (0.1–10.4) 0.76 (0.1–4.6) 4.10 (1.0–17.2) 1.53 (0.4–6.6) 8 7
2.07 (1.4–3.1) 1.69 (1.0–2.9) 2.14 (1.6–2.9) 6.21 (2.9–13.1) 0.71 (0.4–1.4) 5.60 3.6–8.6) 3.57 (2.2–5.9) 2.68 (1.8–4.0) 1.70 (0.8–3.5) 4.60 (2.5–8.4) 2.68 (1.7–4.1) 8.39 3.0–23.2) 2.07 (1.0–4.3) 9.19 (5.5–15.4) 5.96 (3.4–10.5) 8.62 (5.1–14.5) 5.54 (3.0–10.2) 0.28 (0.1–0.5) 0.51 (0.3–0.9) 0.24 (0.1–0.5) 9.29 (5.5–15.6) 0.53 (0.3–0.9) 1.48 (0.7–3.1) 1.10 (0.3–4.0) 15 14
19F 19A 18C 14 9V 7F
1.85 (1.2–2.8) 1.35 (0.8–2.4) 2.06 (1.5–2.9) 3.44 (1.6–7.4) 0.62 (0.3–1.1) 4.45 (2.9–6.9) 2.99 (1.8–4.9) 1.33 (0.6–2.8) 2.82 (1.4–5.9) 2.11 (1.3–3.3) 3.99 (1.4–11.4) 1.49 (0.7–3.0) 7.02 (4.1–12.0) 3.79 (2.1–7.0)
6B 5 4 3
4.30 (2.6–7.2) 0.24 (0.1–0.4) 0.42 (0.3–0.7) 0.24 (0.1–0.4) 7.11 (4.3–11.6) 0.47 (0.3–0.8) 1.14 (0.6–2.2) 1.12 (0.4–3.2)
1
PCV13 serotypes
N GMC, g/mL (95% CI)
Table 3 Geometric mean concentrations (GMC) before and after PCV13 vaccination.
Twenty-four individuals had not previously received PCV13. In this group, the following numbers of individuals (%, range of time since the last dose of PPV23) had received 1, 2 and 3 doses of PPV23, respectively: 12 (50.0%, 0.8–13.0 years), 10 (41.7%, 0.5–6.5 years) and 1 (4.2%, 1.3 years). Mean years since vaccination were 4.6 (0.5–13.0 years). Nine individuals were considered to be immunocompromised for the following reasons: haematological malignancies (n = 5), ongoing immunosuppressive treatment (n = 3, methotrexate or rituximab) and generalized solid organ malignancy (n = 1). All individuals in this group were vaccinated with a dose of PCV13. Two individuals had been vaccinated with a dose of PPV23 within a year of this study but fulfilled our criteria for PCV13 vaccination after receiving the results of the pneumococcal serology analyses (≥2 pneumococcal serotype-specific antibodies 200 cells/L, from the United States and Europe, where the antibody response to a single dose of PCV7 was comparable with PPV23 for the serotypes evaluated [20–23]. Serotypes 1 and 19A had the highest observed pre-PCV13 titres (GMCs > 4 g/mL), but were less prevalent in the population of Scania, Sweden, compared to serotypes 7F, 14, 3, 4, 9V, 23F, and 6B, and only represented 3.4% and 3.7%, respectively, of 436 pneumococcal blood isolates from this population during 2009–2010 [Personal communication]. We observed significant increases in pre- to post-PCV13 pairs of antibody concentrations for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 19F and 23F, and for serotypes 9V and 14 tendencies toward increase were found. In contrast, a slight decrease in post-PCV13 concentrations for serotype 6B was observed. Notably, a dose of PCV13 contains the double amount of serotype 6B (4.4 g/dose) compared to the other serotypes (2.2 g/dose). However, it is possible that an equal or higher response to serotype 6B could be found if the quality of antibodies, e.g. avidity or opsonophagocytic activity (OPA), was measured. In a subgroup analysis of immunocompromised patients, significant increases were found for serotypes 4, 18C, and 23F pre- to post-PCV13 but the number of patients is too small for making any reliable conclusions. Previous studies of asplenic individuals have demonstrated good immunological responses to PCV7. Stanford et al. studied 111 splenectomised individuals, of whom 97% had previously received PPV23 and 70% had received a PPV23 dose within 5 years prior to the PCV7 vaccination study, and observed high serotype-specific IgG concentrations pre-PCV7, with significant increases (p < 0.01) in GMC’s pre- to post-PCV7 for the PCV7 serotypes [16]. MeerveldEggink et al. vaccinated 54 asplenic patients with two doses of PCV7 followed by PPV23 after six months; 76% had received PPV23 in the past, and the mean time since the last vaccination was 8.6 years [24]. They observed significant increases in serotype-specific IgG GMC’s after the first dose for all seven serotypes, no further increases after the second dose, except for serotype 4, and no significant increases were found after PPV23 [24]. Our study has some limitations. Adherence to vaccination guidelines was investigated retrospectively based on patient records, questionnaires and interviews of 69% of living patients. Primary vaccination data were easily found in hospital records, but the collection of revaccination data was based on patient statements.
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There are obvious limitations to this method, but we were able to crosscheck 92% of the statements regarding PPV23 booster doses. Fifteen individuals (31%) did not participate in the study. Due to small numbers of patients in the subgroups, our possibilities for conclusions were limited. The World Health Organisation (WHO) has recommended a protective threshold ≥0.35 g/mL of serotypespecific IgG following conjugate immunization in children [25], but the relevance of this threshold for protection against invasive pneumococcal disease (IPD) in adults is unclear. Pneumococcal antibody levels have been shown to increase with age and inversely the incidence of IPD decreases, except for the elderly; although the proportion of older people with antibody levels ≥0.35 g/mL remains high, the incidence of IPD is elevated compared to young adults [26]. Furthermore, serotype-specific IgG concentrations are not necessarily correlated with the immunity in vivo. It has been proposed that measuring antibody avidity and using functional antibody assays are more appropriate in elderly individuals [27]. Current US recommendations on the use of PCV13 in adults are based on two randomized multicentre studies, that used OPA to measure immunogenicity [11]. In conclusion, adherence to pneumococcal vaccination guidelines in the splenectomy cohort was adequate, at least in terms of primary vaccination. In contrast, vaccination against Neisseria meningitidis serogroups A + C was insufficient. There is a need to improve the awareness among healthcare professionals of the greatly increased risk of severe infection with encapsulated bacteria post-splenectomy and how these infections, in particular overwhelming post-splenectomy infection, can be prevented. In the second part of this study, high levels of serotype-specific IgG concentration ≥0.35 g/mL were observed in previous PPV23 vaccinated but PCV-naïve asplenic patients. Further our results suggest that PCV13 is immunogenic for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 19F, and 23F, if used as a booster dose in asplenic patients with previous PPV23 vaccination. Larger studies are needed to confirm our results, to better evaluate the immunological responses for serotypes 6A, 6B, 9V and 14, and to investigate the immunological and long-term protective effects of PCV13 used as a primary pneumococcal vaccination in asplenic patients. Role of the funding source This work was supported by an unrestricted grant from the Research and Development Committee (FoU-kommittén) at the Central Hospital Kristianstad, Sweden. Conflict of interest statement None of the authors has any conflict of interest relevant to this article to declare. Acknowledgements The authors would like to thank Åsa Möllerstedt at the Clinic for Infectious Diseases for her invaluable help with patient contacts and blood sampling, and Inger Nilsson at the Department for Clinical Chemistry for preparing samples for serology testing. References [1] Werner S, Winstedt D, Kander T. [29-year-old man treated with splenectomy died of pneumococcal sepsis. Important that pneumococcal vaccination of splenectomised is not forgotten]. Lakartidningen 2012;109:1404–5. [2] Holdsworth RJ, Irving AD, Cuschieri A. Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br J Surg 1991;78:1031–8. [3] Davidson RN, Wall RA. Prevention and management of infections in patients without a spleen. Clin Microbiol Infect 2001;7:657–60.
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